Activity Transcript

Chapter 1: Advanced/Recurrent Endometrial Cancer​: A Patient’s Journey Through the Disease Course

Domenica Lorusso, MD, PhD​: Hello, I'm Dominica Lorruso. I am a GYN oncologist working at the Fondazione Policlinico A Gemelli, Rome in Italy. Welcome to this program dedicated to the current challenge and unmet needs in the treatment of advanced or recurrent endometrial cancer. In this multi-part program, Christian Marth and Nicoletta Colombo and myself will be discussing advanced or recurrent endometrial cancer. We will give you an overview of the disease, including the clinical characteristics and current clinical options, but we also will discuss the current challenges in the management of these patients. And how the latest clinical data may help us in addressing this point. In this chapter one, I'm going to talk about a patient journey through the disease course of the advanced or recurrent endometrial cancer.

As you know, uterine cancer is the sixth most common diagnosed cancer in women worldwide. And it is the only gynecological malignancy with an increase in incidence and mortality. It has been calculated [that there are] more than 400,000 new diagnoses every year, and unfortunately, about 100,000 patients die of the disease. Stage of disease as usual is the most important prognostic factor. And most part of our patients, about 80% of them receive the diagnosis with a localized tumor. Tumor confined to the uterus, but also in this case, 15% of patients present some risk factors and added to the 20% of patients who are diagnosed in an advanced stage, means that about 35% of our patients will have advanced or recurrent endometrial cancer.

And now we will focus on the treatment of these patients. There are several recognized risk factors for endometrial cancer. It has been very well recognized that the increased level of estrogens, obesity, type 2 diabetes, older age, family history, the Lynch syndrome and the previous diagnosis of atypical endometrial hyperplasia or breast or ovarian cancer, but also radiation therapy and polycystic ovarian syndrome are all recognized as risks factors that are associated with an increased risk of endometrial carcinoma. But we have also identified some factors that reduce the risk of endometrial carcinoma. For instance, the use of oral contraceptive, the implantation of intrauterine devices and obviously pregnancy.

Usually, the symptoms occur very early. They are typically characterized by postmenopausal bleeding, which is typical of premenopausal, but more important in postmenopausal women. When the symptoms occur patients usually start a workup with ultrasound evaluation, uterine biopsy, and CT scan in order to evaluate the lymph nodal status and if there are distant metastasis.

Then the patient receives surgery. Actually, the standard surgical treatment for endometrial cancer is hysterectomy with salpingo-oophorectomy, and the evaluation of lymph nodal status. Hysterectomy is typically performed by laparoscopy after the publication of the LACE trial comparing laparoscopy or laparotomy and reporting no difference in outcome for patients receiving laparoscopy. The same disease-free survival, the same mortality for sure, with a better toxicity in terms of postoperative complications for patient receiving laparoscopy.

The evaluation of the lymph nodal status has changed in the last year. We do not perform a lymphadenectomy anymore, also because lymphadenectomy has no reported therapeutic role, but we perform the sentinel lymph node, which gives us the information about the lymph node status avoiding for the patient the consequence of an extensive lymphadenectomy. We do not have the level one evidence, I mean randomized trials suggesting that sentinel lymph node is as effective as lymphadenectomy, but we are full of retrospective and observational data suggesting the non-inferiority of sentinel lymph node mapping in comparison to lymphadenectomy. Then we received the pathological report. There are some well recognized risk factors, the grading of the tumor, the myometrial infiltration, the presence of lymphovascular space involvement, the histology, and all these clinical risk factors categorize our patient in risk groups, low intermediate, high intermediate and high-risk group.

But very recently, our guidelines stressed the necessity to perform a molecular profiling of the tumor that should be done at diagnosis because this can integrate the clinical characteristic and identify better stratify our risk factor group. So, in this moment, endometrial cancer remains the only gynecological malignancy with the rising incidence and mortality. For recurrent and advanced disease, the 5-year survival rate is only 17%. For several years, carboplatin paclitaxel has been the standard of treatment for first line therapy, but when patient progress after carboplatin paclitaxel, no standard second line therapy has been identified. And whichever drug we use, the response rate is about 10 to 15%.

But endometrial cancer was a Cinderella and Cinderella wakes up and becomes a princess. And this occurred when the TGCA project clearly reported that endometrial cancer is not a single disease. They are not 2 different tumors as we believe for several years, but actually we have 4 different tumors with different clinical characteristics, different molecular profiles and different treatments probably. And in the next chapter we will have more information about that. Thank you for participating in this activity and please continue and listen to the next chapter in this program. Thank you.

Chapter 2: Who is in Your Clinic? ​Understanding the Clinical Characteristics of Advanced/Recurrent Endometrial Cancer ​

Christian Marth, MD, PhD​: Hello, my name is Christian Marth. I'm a gynecologist from the Medical University in Innsbruck in Austria, and it's a pleasure for me to discuss with you the role and the characteristics of advanced recurrent endometrial cancer. When we look back at 2015, when we published our penultimate guideline on endometrial carcinoma, we used very simply system, or we looked only in the microscope, and then we said, "Oh, this is a high-risk or a low-risk tumor." But nowadays, we know that there are several types of endometrial carcinoma. We have at least 4 groups of histology, endometroid, we have the serous, we have the clear cell, we have other rare types of histology.

But more than that, we know that there are several other factors important for describing the endometrioid carcinoma. We know that the grading is important. And in addition to that, also the molecular classification. We know that hormone receptors play a role, mismatch repair deficiency. The mutation in the important tumor suppressor gene P53. This has mainly been published and presented by the Cancer Genome Atlas 2013, when we learned that we have 4 groups of endometrial carcinoma. We have the POLE ultramutated tumors, with a lot of mutation throughout the genome. We have the microsatellite instable, the mismatched repair deficient tumors. We have those, on the other hand, the copy number high serous like tumors, which are mainly driven by P53 mutation. Then in the middle, we have the copy number low endometrioid carcinoma.

When we look in the algorithm now, which has been also shown in the last guideline by Ana Oaknin, you see that we start with a molecular analysis on all endometrial carcinoma in the beginning, on the first diagnosis. And we look whether there is a pathogenic POLE mutation. If the tumor is POLE wild type, we should look for mismatch repair deficiency, mainly by immunochemistry and looking for the 4 proteins. If the tumor is mismatch repair proficient, and the observation of the P53 expression, again by IHC, will characterize a tumor, which is P53-mutated, or abnormal, or it's a non-specific molecular profile.

It's important to mention that, if we find a P53 mutation or mismatch repair deficiency, but simultaneously, also a POLE mutation, then the tumor is going to the POLE-mutated group, because this is then the driver mutation, and the other one is only passenger mutations. This characterization is important, because it's a major prognostic relevance. Several authors have shown that patients with a POLE mutation have an almost 100% 5-year survival rate. Those tumors with a P53 abnormality have a very poor outcome, with approximately 50% 5-year survival or recurrence-free rate. But the mismatch repair deficient and the non-specific molecular profile tumors are lying in between.

But more than that, and I think that's very important also, for the next presentation, when we are thinking about the treatment, that this molecular characterization helps us not only to define the prognosis, but more than that, also is a predictive factor for the treatment. So again, POLE-mutated tumors have such a good prognosis that they don't need any additional therapy. P53 abnormal tumors have a poor prognosis, and they need chemotherapy, also in addition to radiotherapy, to gain the best outcome. For mismatch repair deficient tumors, the addition of chemotherapy to radiotherapy did not show any benefit. And for those with an NSMP tumor, there might be some benefit by adding chemotherapy, and in future, maybe also other agents could play a role for this group.

However, it's not only those molecular profiles which has been presented so far, may be also other factors could play a role. I would like to mention only tumor mutational burden, since it has been shown that those tumors with a high tumor mutational burden express a lot of immune associated new antigens, and these might behave like a mismatch repair tumor, and therefore, be candidate also for immune therapy.

But all these details will be given now in the next presentation. I would like that you stay and continue and listen to this next chapter given by Professor Colombo.

Chapter 3: Overview of Current Clinical Options and the Clinical Evidence to Support Therapeutic Indications ​

Nicoletta Colombo, MD, PhD​: Hello, everyone. My name is Nicoletta Colombo from University of Milan-Bicocca, and I am the director of the Program of Gynecological Oncology at the European Institute of Oncology Milan. My role today will be to [give an] overview [of] the clinical options and also the clinical evidence to support the therapeutic indications for patients with advanced endometrial cancer. You have heard already that this is the most common gynecological cancer in the developed world and also the only gynecological cancer with rising incidence and mortality.

The ESMO clinical guidelines were recently published, and basically, for recurrent metastatic endometrial cancer, you have, as a first-line treatment, 2 options. The first is for low-grade carcinoma with endometrial histology and low-volume indolent disease, the first option is hormonal therapy. For the other patients, the first option is chemotherapy with carboplatin and paclitaxel. When we go to recurrence, then I think it's important to differentiate tumors with microsatellite instability or mismatch repair deficiency from those with microsatellite stability, because in the first situation, you may use a second treatment rechallenge with platinum base, you may use other chemotherapy, such as doxorubicin or paclitaxel, but also, you do now have the option to use dostarlimab and/or the combination of pembrolizumab and lenvatinib. For patients with microsatellite stable disease, then, again, you have the option of rechallenge with carboplatin-paclitaxel or to use a different chemotherapy such as doxorubicin or paclitaxel, and if you want to use immune checkpoint inhibitors, you have to use it in combination with lenvatinib. So, the treatment of choice will be pembrolizumab and lenvatinib.

Let me review briefly the evidence for these recommendations. First of all, hormonal treatment, we know that patients with low-grade tumors, indolent tumors, they may respond very well to hormonal treatment. Actually, besides the progestin therapy and the aromatized inhibitor therapy, there is now evidence from a phase 2 that the combination of palbociclib with letrozole may be even better than letrozole alone, and a phase 3 trial is now planned for the future. In terms of chemotherapy, the standard of care is still carboplatin and paclitaxel, and this is based on GOG 209, which demonstrated the equivalence of the 2-drug regimen compared to the 3-drug regimen including carboplatin, paclitaxel, and anthracycline.

Now, we heard now that there is a new classification of endometrial cancer, and you may differentiate what we call hot tumor from the cold tumor. The hot tumors are the poly-mutated or the MSI-high, and these are the tumors which may respond very well to immunotherapy. In fact, we do have this evidence from pembrolizumab and dostarlimab that this can be extremely effective in patients with this kind of tumor with deficient mismatch repair. Dostarlimab was the GARNET study. It was a phase 1b expansion phase trial, where both patients with deficient mismatch repair and proficient mismatch repair tumors were included. In those with deficient mismatch repair tumors, 143 patients, the response rate was 45.5%. Even more importantly, with a very long follow up, the median duration of response has not been reached and the probability remaining in response at 24 months was 83.7%. If you look at the progression-free survival curves, it's very interesting to see that you have a rapid drop at the beginning, but then you see this flattening of the curve, which is very, very encouraging. And the same is also true for overall survival. So, high response rate, but particularly, a long duration of response rate, which translates into a longer progression-free survival and overall survival.

If this is the case for tumors with deficient mismatch repair, the single-agent IO efficacy in patients without mismatch repair deficiency tumors is quite low. Then, in this case, we need combinations, and for sure, one of the most interesting combinations is the combination of pembrolizumab and lenvatinib. There is a strong rational for this combination because we know that VEGF creates a very immunosuppressive microenvironment by inhibiting T cell function and also stimulating Treg.

So, it makes sense to combine these 2 drugs. This was done and was tested prospectively in a phase 3 study, which is the KEYNOTE-775, where lenvatinib plus pembrolizumab was compared to standard of care, second-line chemotherapy with doxorubicin or paclitaxel in patients previously treated with platinum with recurrent metastatic endometrial cancer. The trial was extremely positive, both in the proficient mismatch repair tumors and in the all-comers population in terms of progression-free survival, where there was a significant improvement in progression-free survival, but also, and even more important, in overall survival. So, there was a significant improvement in overall survival in patients with proficient mismatch repair tumors, but also in the all-comer population.

Now, what is interesting though is that even the population with deficient mismatch repair had a great benefit from the combination of pembrolizumab and lenvatinib, and that's why, in the ESMO guidelines, this combination is also considered for patients whose tumor is mismatch repair deficient. In this trial, also we observe an improvement in response rate. There is almost doubling of response rate and the duration of response were much longer with a combination of pembrolizumab-lenvatinib compared to standard of care chemotherapy.

Just a warning about toxicity. The combination, for sure, has toxicity and some of this toxicity may be difficult to manage in patients who are typically old and with several comorbidities. Particularly, hypertension was very, very frequent, 64% any grade, but particularly, almost 40% grade 3. And then we have hypothyroidism, diarrhea, nausea, and so on. So, it's a very effective treatment, but of course, you have to pay attention about the possible toxicity.

This combination was approved both by the FDA and by the EMA with a slightly different indication, because in US, it was restricted to patients without deficient mismatch repair tumor only, in Europe, instead, it was approved for all patients and that's why the ESMO clinical guidelines include this possibility also for patients with deficient mismatch repair tumor. So, of course, the difficult part would be to choose whether to use single-agent or combination in patients with deficient mismatch repair tumor. I think my personal opinion, since the results with single-agent IO are so good in patients with deficient mismatch repair, my choice would be to go for single agent in this population because of toxicity, mainly, because of course, as I said, that 2-drug regimen is more toxic. So, maybe we can avoid this toxicity in patients with deficient mismatch repair tumor and just limit the combination to patients with microsatellite stable tumors or proficient mismatch repair tumors.

Thank you very much for listening and now we are going to have some discussion altogether, and thank you

Chapter 4: The Need for New Therapeutic Options to Address a Clinical Gap and Maximize Care ​

Domenica Lorusso, MD, PhD​: Hello, I'm Domenica Lorruso. I am a gynecologic oncologist at the Fondazione Policlinico Gemelli of Rome in Italy. Joining with me is Christian Marth, professor and head of the Department of Obstetrics and Gynecology at the Medical University Innsbruck in Austria, and Nicoletta Colombo, Director of the Program of Gynecologic Oncology at the European Institute of Oncology and at the University of Milano-Bicocca in Italy. In this chapter, we are going to discuss the need for new therapeutic options to address a clinical gap and maximize care in advanced and recurrent endometrial cancer. And I'd love to start with you Christian, with the first question, in your opinion, what are the current challenges in managing patients with advanced or recurrent endometrial cancer?

Christian Marth, MD, PhD​: The problem we see is that our conventional treatment results in low response rates, we have high rates of progression, short duration of response, and finally low overall survival rates. And also, re-treatment with for example, platinum-based therapy, in contrary to for example, ovarian cancer, results in very poor outcomes. So, what we definitely need is treatment which gives us a higher response rate and especially also a long duration of this response.

Dr Lorruso: And possibly with a reduced toxicity with respect to chemo?

Dr Marth: Yeah, maybe, that's also an important factor to focus on.

Dr Lorruso: This is very important, because we are in the moment in which immunotherapy is taking place in the endometrial cancer treatment. And Nicoletta, what is in your opinion, the role of immunotherapy in the adjuvant setting?

Nicoletta Colombo, MD, PhD​: Well, given the excellent results that we achieved in the advanced setting, I think it is rational to look at the role of immunotherapy in the adjuvant setting. And actually, 2 studies, very important, one already completed the accrual, and this is the of ENGOT-en11/KEYNOTE B21, and was a randomized study looking at the addition of pembrolizumab to chemotherapy in the adjuvant setting with or without radiotherapy. The study enrolled 1,090 patients and the accrual completed in October 2022, so we [are] just waiting for the results.

The other study is just starting, and actually it's not one study but there are 4 studies, it's called RAINBO, and according to the molecular profile of the tumor, 4 different options will be tested. So, in patients with a p53 abnormal tumor, the addition of olaparib to standard of care will be tested. In patients with a mismatch repair deficient tumor, the addition of durvalumab will be tested. In the non-specific molecular profile, [patients will be treated] with estrogen receptor positive hormonal treatment. And finally, in POLE-mutated [tumors], no treatment will be applied. And so, we will prospectively confirm whether these patients do not need adjuvant treatment.

Dr Lorruso: So, the role of immunotherapy is expanding more and more, and in other solid tumors immunotherapy is replacing chemotherapy. Thinking about colorectal cancer in MSI-high patients, immunotherapy actually is replacing chemotherapy in the first line treatment, and we are exploring the same concept also in endometrial cancer. We have 2 randomized trials comparing pembrolizumab vs the standard of care, carboplatin paclitaxel, in en15 trial. But also in the DOMENICA trial, we have dostarlimab vs carboplatin paclitaxel in advanced or recurrent endometrial cancer patients, chemo-naive patients with MSI-high endometrial tumors. So, the idea that in the future, immunotherapy will replace chemotherapy in the first line advanced setting.

And Christian, immunotherapy alone works very well in MSI-high patients and Nicoletta showed how well works the combo of pembro-lenvatinib in MSS population. You are the PI of a very important trial evaluating this topic, in your opinion in the coming future, the combination of pembro-lenvatinib will replace chemotherapy in the frontline setting, and if so, for all patient or only for MSS?

Dr Marth: Yeah, I think that's a very important question, because looking forward, we concluded the ENGOT-en9 and the LEAP-001 trial in which we really ask this question, and we randomized patients upfront for the old chemotherapy carboplatin paclitaxel and randomized them vs pembrolizumab plus lenvatinib. And both groups of patients, mismatch repair deficient and proficient, have been enrolled. So, we are waiting for the results, but it'll deeply depend of course on how effective this combination will be in comparison to the chemo.

In second line, it was obviously superior. In the first line, we are comparing with a more active regimen, carboplatin paclitaxel is more active than the second line chemotherapy. So, this will be a hard battle to fight and we are waiting for the results. But if this is coming out that we can improve overall survival, then for sure this combo could play a role in the first line therapy, especially for mismatch repair proficient. For the mismatch repair deficient as already has been mentioned, single agent is very effective and has a reduced toxicity because this is a major point. So, I think in the end, the data will clarify what is the role of the combo in which group of patients.

Dr Lorruso: Yes, absolutely. But we are exploring also another concept, I mean the combination of immunotherapy plus chemotherapy, and Nicoletta is the PI on one of the trials exploring this concept. And Nicoletta, I would like to ask you if in your opinion this strategy, chemo plus immuno, will replace chemotherapy alone in endometrial cancer patients with advanced or recurrent disease?

Dr Colombo: It may well be the case, because there are 3 randomized phase 3 trials which investigated a very similar question with 3 different drugs. So, the question is, addition of ICI to chemo carboplatin paclitaxel, in RUBY dostarlimab, in NRG-GY018 was pembro, and in the ATTEND study was atezolizumab. Very similar, very similar design. All of them completed the accrual, and for 2 of them we had a press release announcing a positive result, and this will be presented at the SGO very soon.

So, I think this will be probably a new challenge, because then we may even have to reconsider the design of the other study we discussed. For instance, the DOMENICA study, is chemotherapy alone the standard of care or the new standard of care will be chemo plus immunotherapy? So, I think this is very challenging, this is an exciting time. Of course, when we have positive data, we are all very happy for our patients. But yes, we have to be very close to the new results and see what the future will serve to us.

Dr Lorruso: Yes, and the challenge can be even more tricky, because we are exploring another possible combination which is the combination of chemo plus immuno plus PARP inhibitor. We have some data coming from phase 2 trials suggesting an additive, possibly a synergistic effect, when we combine immuno plus PARP inhibitor. And we know that some of p53-mutated endometrial cancer patients present homologous recombination impairment. So, 2 trials are exploring the combination of dostarlimab plus niraparib plus chemotherapy, the RUBY 2, or durvalumab plus olaparib plus chemotherapy in primary advanced and recurrent endometrial cancer. So, the future is very, very interesting and unpredictable as you said.

And there is the last strategy that we are exploring, is the maintenance. The concept of maintenance in endometrial cancer was never explored, but actually we have some trials exploring them. Nicoletta, what is in your opinion the role of maintenance therapy after systemic chemotherapy in endometrial cancer?

Dr Colombo: Yeah, moving away from immunotherapy, now we are talking about a completely different drug, which is selinexor, which is Exportin 1 inhibitor. So, the major mechanism of action is that as you know, we do have tumor suppressor proteins such as p53, and this Exportin 1 is the major nuclear export protein for these tumor suppressor genes. So, the inhibition can increase in the nuclear level the activation of tumor suppressor genes, and this is very important. We have preliminary data which are quite interesting, particularly from a phase 2 study, which was negative in the essence, but in the subgroup of patients with p53 wild-type, we saw a very interesting signal of efficacy. And that's why now we plan a phase 3 study only for patients with p53 wild-type tumors. And again, this drug will be tested as maintenance after chemotherapy for patients with advanced recurrent endometrial cancer.

Dr Lorruso: Very interesting concept, also very, very interesting discussion. Thank you, Nicoletta, and thank you Christian for this great discussion, and thank you for participating in this activity to all of you. And please continue to answer the question that follow and complete the evaluation form. Bye.

This transcript has not been copyedited.