 Let’s move on to KEYNOTE-146, which I refer to as LEN-PEM because it gets a little difficult to say lenvatinib and pembrolizumab. Dr Vicky Makker reported the final analysis that was published in the 

], looking at and diving down into the different aspects of these patients. When we look at the final report, Vicky does a wonderful job describing that there is a difference between patients who have received prior chemotherapy for adjuvant vs patients who have just received carboplatin-paclitaxel for recurrent disease. Meaning: If they have recurrent or advanced disease, they get carboplatin-paclitaxel and then move right into lenvatinib-pembrolizumab compared with a patient who received carboplatin-paclitaxel as adjuvant and then recurs and gets the agents of lenvatinib-pembrolizumab.

In the total population of patients, we see a response rate, depending on the report, of about 37% to 38%. We see this 37% to 38% in the entire cohort of patients, which is just under 100.

Dr Makker does a wonderful job in the most recent report looking at the differences between patients who have been treated with carboplatin paclitaxel vs those who received adjuvant therapy.

This is very interesting. When we look at the population of patients, the patients who received carboplatin-paclitaxel and then went right into LEN/PEM [lenvatinib-pembrolizumab] had a response rate of 41%, while the patients who had previously received carboplatin-paclitaxel for adjuvant and local-regional disease as the adjuvant setting had a 57% response rate. When we add up the numbers, they’re slightly different because there’s another group of patients who had more than 1 prior therapy, and that group of patients is going to be a little lower. So the entire population is about 37% to 38%.

Those who went right from carboplatin-paclitaxel are at about 41%, while those who received previous adjuvant therapy are at 57%. What does that mean to me? That means I always quote to my patients 37% or 38% response rate. But if I take a patient who had received previous therapy of carboplatin-paclitaxel for adjuvant, their response rate is up to about 57%. This is a small group of patients. We need to see the confirmatory trial, which will hopefully be reported shortly to drill down into this answer.

The toxicity with LEN/PEM [lenvatinib-pembrolizumab] is real. You have all the associated I/O [immuno-oncology] toxicities, then you bring in lenvatinib. So let’s talk about the I/O–associated toxicities. We need to learn from our lung cancer and melanoma experts because they have so much more experience with these agents. When I discuss with a patient the toxicity associated with pembrolizumab or other I/O agents, I talk about a 30% to 40% chance of an I/O-associated toxicity, which would require me interrupting treatment and potentially giving steroids. Of that 30% to 40%, 5% to 10% will have toxicities that will potentially require hospitalization.

We’ve gotten better at managing these toxicities, so I suspect that number is closer to 5% now. But within that population, we have about 1% to 2% of patients who will have life-threatening or life-altering toxicities. Somebody becoming a type 1 diabetic or losing their function of the pituitary is life altering. That’s rare. But if it occurs, it is obviously life altering. Combining with that lenvatinib, what are the other challenges with lenvatinib? Hypertension, diarrhea, some skin changes can be an issue, hair changes, some whitening of the hair. The ones I worry about are the diarrhea and the hypertension.

These are patients who I give the antidiarrhea directions to and make sure they have the medications at home. We also give them the prescription. I have colleagues who make them fill a prescription so they have something at home while we give them the prescription, because we always know these high blood pressures occur on the weekend without our usual team in place. We give the patient a prescription if they need them, and we make sure we have them monitored closely. What else have we done? We’ve instituted weekly videoconferencing with the patients. One thing that has come out of the COVID-19 [coronavirus disease 2019] era is the ability to perform videoconferencing.

We now have once-a-week videoconferencing for the first cycle and potentially second cycle to make sure we’re on top of these toxicities. You have to remember that about 80% of patients on lenvatinib-pembrolizumab will require dose reduction. Some people would argue 88% if you include the dose interruptions. The usual starting dose is 20 mg. That’s the recommended dose. Personally, 20 mg can be a challenge because they get only two 10-mg tabs.

If you dose reduce, you’re going right from 20 to 10 mg, and I’m telling you that 70% to 80% are going to be dose reduced. What we do is order the 18 mg. That comes with a 10-mg tab and two 4 mg tabs. I feel much more comfortable with a 10% adjustment from 18 to 20 mg. It’s unlikely that we’re impacting efficacy. Then when that patient needs to be dose reduced, I can dose reduce according to the package insert down to 14 mg, and if I need to go down to 10 mg, they still have that option.

Videos

Safety/Efficacy Results From EC Cohort of KEYNOTE-146

 I just finished talking about monotherapy immunotherapy and how landscape changing and world changing it has been for women with mismatch repair deficient [dMMR] recurrent endometrial cancer, which is about 30% of women who present. You see that across the board in studies. That’s really important, but what about the other 70% who don’t have mismatch repair deficiency? Are they just left with our standbys of doxorubicin and weekly paclitaxel with expected response rates of 15%? That hardly seems fair. Fortunately, they are not left with that. They actually have an equally good option, also accelerated approval, and hopefully will be confirmatory approval very soon with the combination of pembrolizumab and lenvatinib.

This is a really interesting combination. Dr Vicky Makker from Memorial Sloan Kettering Cancer Center has led developments of this combination in endometrial cancer. This originally was an investigator-initiated trial. Those of you who run IITs [investigator initiated trials] know that they can sometimes result in tremendous opportunities for our patients; this is an example. Congratulations to Dr Makker, who recognized that both drugs individually had some efficacy. Lenvatinib, just to remind you, is an oral tyrosine kinase inhibitor that targets a number of things: VEGF1, VEGF2, VEGF3, FGFR, PDGFR, BIK, and MEK. I may be even forgetting 1. It’s kind of a dirty tyrosine kinase inhibitor, mainly acting in an antiangiogenic space. We know from prior studies that antiangiogenic agents have efficacy in endometrial cancer. A very large, over 100-patient, single-arm phase 2 was done with single-agent lenvatinib with a response rate of 14%. It has some activity, certainly, but it’s not overwhelming.

Similarly, if you look at pembrolizumab in microsatellite-stable patients, or those patients who don’t have mismatch repair deficiency, you see a similar response rate. It’s about 10% to maybe 15%. There is some efficacy with each drug, but it’s not great in a microsatellite-stable population.

There’s a lot of rationale for combining them. When you think about that VEGF, it is a drug that promotes angiogenesis, and that’s how we all think about it, but it’s also incredibly immunosuppressive. If you have high levels of VEGF around your tumor, you’re creating a microenvironment that is incredibly immunosuppressive with high levels of immunosuppressive macrophages or Tregs but not a lot of cytotoxic CD8 cells. When you block VEGF with tyrosine kinase inhibitors—cediranib is very good at this, lenvatinib actually may be a little better—you’ll not only block the antiangiogenic effect but also convert this immunosuppressive environment into a less immunosuppressive environment, allow more CD8 T cells to come in, and by doing so enhance the efficacy of immune agents such as pembrolizumab.

This was demonstrated in elegant animal models and then moved into IIT that I talked about, which was a single-arm study that launched in a few centers in the United States and used the combination of lenvatinib and pembrolizumab in patients who had disease that had recurred after frontline paclitaxel and carboplatin. So many patients were enrolled who were mismatch repair deficient, but most of the patients were mismatch repair intact. They found a remarkable response rate in this group of patients who heretofore had nothing active in their toolbox. They had an overall response rate of almost 40%, several standard deviations above what would be expected with standard options.

In addition to this, about 11% of patients had complete response rates, which is something we had never talked about in this disease space. Suddenly, we’re putting patients into some kind of a remission, which is pretty remarkable. At the time this was presented, the duration of response had not been reached, but it’s right about a year, with most responders going well beyond 6 months.

When you look at the breakdown among the different histologies—and these are small numbers, so we can’t hang too much on it— it is quite exciting. There were 5 patients who had clear cell tumors and each of them had a reduction in their tumor size. Not all of them were a RECIST response of a 30% reduction, but all of them had a reduction in their tumor size. If you looked at the patients who were classed by the serous, their response rate was even higher than the overall group. So this combination appeared to be synergistic in a group of patients who would not be expected to respond to immune checkpoint inhibitors alone.

This got very quickly accelerated approval, not only in the United States, but simultaneously in Australia and Canada as well through a very interesting program. As with all accelerated approvals, there was an ongoing confirmatory trial that compared the combination vs standard medicines, but we have not seen the data. We hope to see it in spring, but the press release has just come out and stated that it met the primary end points and was superior. The anticipation is that this will receive confirmed approval and then hopefully will be available outside the United States as a global approval as well, which is an incredibly important advance for women with recurrent disease. We have 2 options now based on molecular subtypes, both of which with a high likelihood of helping patients for a durable period of time. That’s a world of difference from where we were a few years ago.

Rationale for Combination Therapy in Advanced EC

 One of the most exciting developments in the field of therapeutics for endometrial cancer has been immunotherapies. We’ll talk quite a bit about monotherapy immunotherapy in this module, then later we’ll talk about combinations. For women whose tumors harbor mismatch repair deficiency [dMMR], microsatellite instability [MSI], and maybe even tumor mutational burden [TMB]—that’s not a validated biomarker yet, but we’re certainly looking at it—use of monotherapy immunotherapy has been a game changer for women with recurrent disease.

Prior to the pembrolizumab approval, there was nothing FDA approved. Our options for second-line treatment of endometrial cancer was doxorubicin or weekly paclitaxel. We have phase 3 data for both of those agents in that setting with a response rate of 15%. That’s the best our patients could expect. There wasn’t really an option for third-line treatment of endometrial cancer because our patients, unfortunately, weren’t living to third and fourth line. When you think about it, that’s not too long ago. Now we’re in this immunotherapy era. It’s such a different environment for our patients, thankfully, with monotherapy immunotherapy.

Pembrolizumab was the first to get approval based on a very large basket trial, and some patients with MSI-high endometrial cancer were included, which was fantastic. Now we have dostarlimab. The GARNET study was presented in 2019 and published in 

 in 2020. This was led by Dr Ana Oaknin from Spain. The GARNET study was a huge phase 1 study looking at the efficacy of dostarlimab, which is an anti–PD-1 monoclonal antibody, in patients with recurrent endometrial cancer. They had a number of molecular cohorts, but the 1 we’re talking about today is those patients who have deficient mismatch repair proteins or microsatellite instability. They also had to have had at least 1 prior line of chemotherapy. This is second line and beyond recurrent disease.

This is a very large study. They accrued over 100 patients into this study, so it’s a very large safety database as well as an efficacy database. The efficacy was what we would expect in this population: fantastic. If you look at the 71 patients who were confirmed deficient mismatch repair, the complete response rate—which I don’t think we’ve ever talked about in this disease setting—was almost 13%, with an additional 30% being a partial response. The overall response rate was about 43% or 44%. An additional 15% to 16% were stable disease, which often can also be a win in this disease setting if it’s long-standing. The duration of response was so long that it wasn’t even reached, so we can’t report that at this time.

The other thing that’s important to note is that because this was such a large study, we have nice data for safety. The safety was what we would expect from this class of agents, with very low rates of immune-related toxicities. Those toxicities are real. As we’ve been using these agents more commonly, we’re all getting more familiar with recognizing them and intervening early to prevent them from becoming severe. The toxicities are uncommon but can be important.

We saw low rates of anemia in this study at about 3%. That’s probably disease related. We saw a very low rate of 2% colitis, which is 1 of the adverse effects we always focus on. And then diarrhea had a rate of only 2%. Those were the grade 3 or higher treatment-related adverse events. That’s a very manageable adverse-effect profile and compelling clinical efficacy. This was 1 of the largest studies done just in women with endometrial cancer, so it gives us a really nice data set, proving what we all suspected: This is an active drug.

We’re hopeful that dostarlimab will gain accelerated approval in this setting and be available for us to use in addition to pembrolizumab. It’s always great to have more than 1 option for our patients. From a cost standpoint, for whatever reason, drugs are slightly different from one another. If 1 is working but not tolerable, another may be tolerable. We don’t have data for that, but we’ve certainly seen that with other classes of drugs—PARP inhibitors, for example. Some people tolerate 1 and not the other. We’ve certainly seen that with tyrosine kinase inhibitors. Having more than 1 similar asset available in a disease space is important for a number of reasons—most important access, so that everyone, if for whatever reason that they may not be able to access 1 drug, can get the other and benefit from durable, tolerable efficacy. This is really exciting. Congratulations to this study team.

GARNET Clinical Trial Regimen in Advanced Disease

 As we look at the data in MSI [microsatellite instability] high from KEYNOTE-158, I was honored to present this at last year’s ESMO [European Society for Medical Oncology Congress] in a featured poster. This data has now been published in the 

], looking at response rates in MSI-high endometrial cancers of 57%. That was markedly better than the original reports, which were about 35% to 37%. As we look at these patients, the clinical benefit is beyond the objective response rate of 57%, with most patients achieving some clinical benefit.

It’s very important when evaluating the biomarkers—at the very least in recurrence, but you could argue at the time of diagnosis—to know what the mismatched repair protein expression is. It’s very important if that is with advanced disease. I would argue to also check PCR [polymerase chain reaction] for MSI.

The impact of pembrolizumab availability has been marked. We previously didn’t have a decent second-line drug for endometrial cancer. It has completely changed the way I look at a patient with recurrent uterine cancer. I’ve always said there’s no possibility of curative intent in recurrent cancer. But now I have to think twice before I say that. When looking at this 57% or 58% response rate, about 10% plus or minus will get complete responses.

All of us who use these agents have several patients with recurrent uterine cancer in our practice who have been cured. We are in a completely new world, and all of us who treat these patients see this. To deny a patient who has MSI-high or an MMR [mismatch repair]–deficient uterine cancer the access to pembrolizumab, I would argue, is not adhering to standards of therapy.

Let me clarify 1 point. When I was talking about access to pembrolizumab for patients who are mismatch repair deficient, I was talking about patients who have recurrent tumors or who have already been treated with carboplatin-paclitaxel. Combining pembrolizumab with carboplatin-paclitaxel has not been adequately studied. Ongoing trials are evaluating whether it adds to carboplatin-paclitaxel. When I’m referring to pembrolizumab for mismatch repair–deficient patients, I’m referring to the recurrent setting. I would not recommend utilizing it instead of carboplatin-paclitaxel at the current time.

Many people ask me what other tumor markers are checked, such as PD-L1 expression and TMB [tumor mutational burden]. I’m pretty adamant about not checking PD-L1 expression. It has not been shown to be predictive in uterine cancer, and we don’t have an indication. TMB is a different story. Do I send it separately? Not usually, but if it’s part of a commercial package. When I check NGS [next-generation sequencing], I definitely will include it. Obviously with the indication in pembrolizumab, I haven’t found that if somebody is an MMR-proficient tumor that they are then TMB positive, but it’s probably worth checking if you’re sending it off. I don’t normally check it separately.

Second-Line Checkpoint Inhibitor for MSI-H Disease

 I mentioned that our understanding of stage in a recurrence and now our emerging understanding of the molecular subtypes is really impacting how we assign adjuvant therapy with the diagnosis of endometrial cancer. You can look at 2 recently published manuscripts that come from different eras to get a sense of this. We’re excited that we saw Gynecologic Oncology Group [GOG] protocol 0209 finally published in 2020 by Dr David Miller. Congratulations.

However, this study was done over a decade ago. They enrolled women with advanced or recurrent disease. These could be patients whom we would consider adjuvant treatment—maybe they had a surgery with a positive node, all the way to stage IV disease. They randomized them to receive paclitaxel and carboplatin, which was the experimental arm at that time, vs the standard of care at the time, which was the triplet of paclitaxel, doxorubicin, and cisplatin given over 2 days. It was a noninferiority design and paclitaxel and carboplatin was found to be noninferior and, therefore, an established standard of care that many of us had moved to already many years ago. But now we have the data to back that up. When you look at the stratification in that study, there was no mention of molecular subtyping. We just weren’t doing that in that era.

Fast-forward to another publication from this year, which was the PORTEC-3 trial. This was a European study that was questioning the benefit of adding chemotherapy to radiation therapy in patients with stage I through III disease as adjuvant therapy. They did extensive molecular profiling as an exploratory analysis in about 500 women. They looked at the markers that I previously mentioned in this module. They looked at loss of 

, and mismatch repair deficiency. They also had a group of patients in whom no significant mutations were found. They looked at the prognostic significance of those 4 classifications then they looked at the significance of those classifications on whether a patient received chemotherapy with their radiation therapy.

As I mentioned previously, the groups definitely were prognostic. When you look at the patients who had loss of 

, their 5-year recurrence-free survival was only 48%, compared with 98% for women whose tumors had a 

 mutation, 72% for women with mismatch repair deficiency, and 74% for those with no significant mutation noted. There definitely is a prognostic significance associated with 

Layered on to that are suggestions of predictive biomarker potential with these markers as well. If you look at the patients with loss of 

 who did or didn’t receive chemotherapy with their radiation—everyone received radiation—the 5-year recurrence-free survival for chemotherapy was 59% vs only 39% if they only received radiation. This group of patients may receive more benefit from chemotherapy than those who don’t have a loss of a 

, they all did so well that it was hard to show a difference. It was 100% vs 97% for chemotherapy vs no chemotherapy. If you looked at the patients with mismatch repair deficiency, it was 68% 5-year recurrence-free survival with chemotherapy vs 76% without. Those are pretty close. The confidence intervals overlap, so it’s probably not significant. The question we need to answer is whether we need to use chemotherapy in that group. Similarly, for those patients with no significant mutation profile, there wasn’t a statistically significant difference in the response.

This is an exploratory analysis so we can’t hang our hat on this, but if you look at the group of patients who have loss of 

, the difference between 59% and 36% is a striking difference in recurrence-free survival and may give us more insight into who needs adjuvant chemotherapy with or without radiation with endometrial cancer.

If you think back to GOG-0249, which was based on high-intermediate risk criteria and added chemotherapy to radiation vs radiation alone, it did not show a difference in this high-intermediate risk group. Maybe that’s because we were still including a group of patients who were just too low risk for recurrence. It’s really focusing on potentially this group of patients with loss of 

. That may be the group who needs chemotherapy. That will have to be validated in a study designed around that end point, but this PORTEC-3 exploratory analysis is certainly a step in the right direction. From a practice standpoint, being off–clinical trial gives you some information about when you add chemotherapy and when you potentially don’t need to in these patients. It’s very important information. I’m glad this was published this year.

Adjuvant Chemotherapy +/- Radiotherapy: Recent Data

 The challenges of advanced disease of uterine cancer are most profound in that we still continue to hang with the history of radiation therapy. Historically, all these tumors were treated with radiation therapy. But every time we do a trial comparing radiation with chemotherapy or radiation with observation, we’re called into question the importance of radiation. With the recent PORTEC-3 trial, we now see that the combination of radiation and chemotherapy may provide benefit. But one could argue that radiation did not add much; it was the chemotherapy.

Some of the challenges we need to look at are: What’s the most important modality, and how many modalities do we need? The most important modality is chemotherapy, but radiation may play a role—especially in locoregional disease, meaning lymph node metastasis. What else is challenging? If we have locoregional disease only with curative intent, how much do we have to do it? Is radiation alone enough? Do we even need radiation? Is chemotherapy alone enough? Are there patients we could just observe after surgery? How about the patients who had a hysterectomy but did not have lymph nodes removed? Do we need to remove those lymph nodes? Every trial we’ve had on surgical staging of patients comes into question, but I digress.

When we’re looking at the advanced uterine cancer and we start thinking about patients who have metastasized beyond the locoregional, their outcomes are very poor. What do we know? The tried-and-true carboplatin-paclitaxel is still our go-to and the basis of each of our backbones of these clinical trials. That’s being questioned with the current LEAP-001 trial looking at lenvatinib and pembrolizumab vs the standard carbo-Taxol [carboplatin, paclitaxel]. We’ll talk about that in a little while.

There are many challenges in the treatment of recurrent uterine cancer. One is that if they’ve already received carboplatin-paclitaxel in adjuvant therapy, should we go back to carboplatin-paclitaxel? Or should we look at some of our new agents, like pembrolizumab in MSI [microsatellite instability] high? Or lenvatinib and pembrolizumab in MSS [microsatellite stable] patients?

We talk about platinum resistance and sensitivity in uterine cancer, but we do that with almost 0 data to influence it. We’ve extrapolated from uterine cancer, but when we really look at it, there’s no way we should be extrapolating. Is there a group of patients I would absolutely put back on carboplatin-paclitaxel? Yes, if it has been years since their prior adjuvant therapy. But as we look at the patients who have received carboplatin-paclitaxel, their response is decreased when they receive it a second time. We need more data on this population. Do I go back to it? Absolutely. Do I have data to support that? No. We need better data to support when we should go back to carboplatin-paclitaxel. I use a lot of the other agents available to us, as far as standard of care or clinical trial—rather than going back to carboplatin-paclitaxel—unless the interval is very long. Is it 2 years, 3 years? Probably 2 years.

Treatment Challenges: Advanced Endometrial Cancer

 We’ve learned a tremendous amount in the past 3 to 5 years about the importance of molecular profiling in patients with endometrial cancer, both in early stage and, probably more important, for treatment selection in advanced-stage and recurrent-stage disease. We’ll talk a little more about that throughout this module.

What we’ve really learned is that all patients, regardless of stage or histology at the time of diagnosis, must have their tumors tested for mismatch repair [MMR] proteins, plus or minus microsatellite instability, and every institution now has its own algorithms developed. I’m pleased to hear that this has rolled out very quickly both in the community and academic centers, so at least patients with a new diagnosis are having mismatch repair proteins tested. This is important because it identifies patients who are at risk for having Lynch syndrome, which is a genetic predisposition to developing endometrial cancer.

Regardless of risk for recurrence, if we diagnose women who have this genetic predisposition, we can prevent them from developing a colon cancer later in their life through appropriate risk-based screening once we’ve cured them from their endometrial cancer. We can do cascade testing for relatives and try to create “previvors” and do risk-reducing surgeries and screenings that prevent them from ever-developing Lynch-associated cancers, which also includes some ovarian cancers. This is incredibly important from a family testing standpoint and prevention standpoint but also in terms of identification of women who will potentially benefit from immunotherapies. We’ll talk about that a little later in this segment.

The same goes for women who are already advanced, have recurrent disease, or are at high risk for recurrent disease. We are testing everyone for mismatch repair proteins. This is less a must, but many of us are doing next-generation sequencing [NGS] for these patients. There, you get tumor mutational burden, microsatellite instability, and 

. You also get some less frequent, but very important from a predictive biomarker standpoint, findings of 

 mutations are less common but still present, and there are others. 

 may be targetable in the future. There are a number of these molecular findings that do impact selection of therapies in the recurrent setting. In the advanced or recurrent setting, next-generation sequencing is certainly warranted.

In terms of thinking about patients who are newly diagnosed and looking at their molecular subtype and histology, we are increasingly understanding the impact on prognosis. For many of you listening to this, it has been a journey. We’ve talked about patients who were intermediate risk if you think back to Gynecologic Oncology Group [GOG] protocol 33, and then high-intermediate risk was determined from GOG-99, based on grade, depth of invasion, and age. We ran clinical trials trying to figure out who was at higher risk for recurrence and how we could impact that recurrence based on risk stratification. Now, when you layer in the molecular profiling on top of that, we have an enriched manner by which we can assess someone’s prognosis and maybe even their appropriateness for adding chemotherapy to radiation therapy in an adjuvant setting based on these molecular subtypes.

When we’re talking about our patients who have loss of 

, that’s mainly going to be your high-grade serous patients but also some high-grade endometrioid, patients who have 

, patients who have mismatch repair deficiency, and a group of patients who have no significant mutations identified. The prognosis in each group varies if you use that group of patients with no mutations as the baseline. Our worst prognosis is among patients with loss of 

. Patients with mismatch repair are somewhat in the middle. We are starting to tailor therapies based on those molecular subtypes and moving a little from our prior way of looking at things by intermediate and high or immediate risk. It’s very much an emerging paradigm for selection of therapy for the right patient.

Genomic Assessments for Metastatic Disease

 It appears that endometrial cancer is actually increasing in its incidence. Why is that? Well, we know as a society we’re getting heavier, and that’s not helping. That only explains the higher number of lower-grade endometrioid cancers. We are also getting older, and as we age, we are seeing higher incidence of these type 2 or high-grade-type uterine cancers. As we age and get heavier as a population, that directly impacts the incidence and prevalence of endometrial cancer.

As the risk stratification of uterine cancer continues to change and metamorphose over time, we still use the classic definitions of histology, endometrioid, serous, and clear cell. Those are still very important. What else are very important? The uterine factors, looking how deep the tumor goes into the uterus, and looking to see if the cervix has stromal involvement. The tubes and ovaries still apply. Those are very important, along with metastatic disease to the regional lymph nodes, or intra-abdominally. That’s extremely important.

What else have we developed? Now we’re looking at the molecular changes in these tumors, and they may predict better than the histologies. 

 expression, mismatch repair [MMR] protein deficiencies, and 

, are all very impactful on the behaviors of the tumors and may be more important than histology.

But I’m not willing to give up histology. As we move forward, we still need to know these important aspects. As we look forward to the different classifications, the TCGA [the Cancer Genome Atlas] started to do this: low mutational burden, high mutational burden, 

. Each of these categories continues to be refined, and some additional data continue to come out that we’re able to apply to the clinical patient population at the direct patient care. Meaning, it’s part of not just research trials but everyday care: 

, MMR deficient, MSI [microsatellite instability] high.

Endometrial Cancer Incidence and Risk Classification

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.

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?

David M. O'Malley, MD, The Ohio State University

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