Therapeutic Approaches in Endometrial Cancer

EP: 1.Heterogeneity of Endometrial Cancer

EP: 2.Biomarker Testing and Multidisciplinary Approaches in EC

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EP: 3.Therapeutic Approaches in Endometrial Cancer

EP: 4.Study 309/KEYNOTE-775 Trial Design

EP: 5.Results from Study 309/KEYNOTE-775

EP: 6.A Discussion on the Study 309/KEYNOTE-775 Data

EP: 7.Experience in Using Pembrolizumab + Lenvatinib in Advanced Endometrial Cancer

EP: 8.Managing AEs With Pembrolizumab and Lenvatinib

EP: 9.Therapeutic Sequencing in Endometrial Cancer

EP: 10.Incorporating Molecular Features into Choosing Adjuvant Therapy

EP: 11.Insight on Ongoing Trials in EC

EP: 12.Novel Targets of Interest in EC

EP: 13.A Look at Surgical Innovations in EC

EP: 14.The Future of Endometrial Cancer Treatment

Brad Monk, MD, FACOG, FACS: Let’s transition now to systemic therapy. Since I have you here, Dave, tell us about this one study, GOG-209, and what that has done to the NCCN [National Comprehensive Cancer Network] guidelines, again, to your point.

David O’Malley, MD: The debate regarding the optimal therapy for metastatic and recurrent endometrial cancer has morphed over the last 15 years with multiple phase 3 trials. Ultimately, what the GOG-209 showed, which was published in the JCO [Journal of Clinical Oncology] last year [2020], was that clearly carboplatin and paclitaxel are the backbone for metastatic and recurrent uterine cancer.

Brad Monk, MD, FACOG, FACS: That is great. I’m going to ask you a question; I’m going to ask Ketta the same question. Do not tell me about every trial; just give me the answer. What is the role of radiation—

I’m coming to you, Ketta, so you get to think here—what’s the role, Dave, of radiation for newly diagnosed adjuvant therapy endometrial cancer?

David O’Malley, MD: Well, I suspect you want my real answer and not the academic answer.

Brad Monk, MD, FACOG, FACS: No, no, lie to me. Lie to me.

David O’Malley, MD: There is no academic reasoning, when looking at the trials in an objective way, to show the benefit of radiation. No trial has ever shown a survival advantage for endometrial cancer and radiation—literally.

Brad Monk, MD, FACOG, FACS: Why do you do it? I know you do it.

David O’Malley, MD: It is dogma; it is hard to overcome dogma. Saying that, the passion, when I see GOG-258, and it increased locoregional recurrence—we do not give radiation. I still have a problem with just stopping with carboplatin and paclitaxel for these patients with locoregional disease.

Brad Monk, MD, FACOG, FACS: That’s why we invented vaginal brachytherapy. Go ahead, Ketta, tell us what the role of radiation is in endometrial cancer. Nicoletta, you can come back to break the tie, if there is one.

Domenica (Ketta) Lorusso, MD, PhD: I fully agree with David; no trial has reported an increase in overall survival due to radiation treatment. Some trials reported better local control, but in most cases, it can be substituted with brachytherapy with a lesser price in terms of toxicity for our patients.

Brad Monk, MD, FACOG, FACS: So in Milan, Nicoletta, is radiation commonly utilized?

Nicoletta Colombo, MD, PhD: I would never use radiotherapy for endometrial cancer—of course we do, but I think the role is quite limited indeed. I am talking about external beam radiotherapy; of course, for brachytherapy, it is different, but I think there is a minority of patients who can benefit from external beam radiotherapy.

Brad Monk, MD, FACOG, FACS: I have got to hear from you too, Vicky. What do you think? What is the role of radiation in the treatment of newly diagnosed endometrial cancer?

Vicky Makker, MD: I wholeheartedly agree with what my colleagues are stating, which is that we have not seen an improvement in overall survival. There are probably a minority of patients who might derive some benefit in terms of local control. However, I wholeheartedly agree with everything that has been said.

Brad Monk, MD, FACOG, FACS: Well, the good news is that it is nontoxic and cheap—not. This is a good consensus. Ketta, let’s transition now to immunotherapy. I think you had mentioned that immunotherapy is what is exciting in the treatment of endometrial cancer. I say, all the time, that immunotherapy works very well when treating cervical and endometrial cancer. It may never work for ovarian cancer, but we have some great opportunities here. Tell us about what monotherapy does for patients who you termed as having MSI-high [microsatellite instability-high] tumors.

Domenica (Ketta) Lorusso, MD, PhD: The problem is that patients with MSI-high tumors have genomic instability. This creates a new antigen and tumor-infiltrating lymphocytes. This constitutes the backbone for which the patient seems to be more prone to respond to immunotherapy. This is what the data reported. In an unselected population when you use immunotherapy, the responses are quite low—about 10% or 15%. When you select according to MSI-high tumors, the response increases significantly, going up to 54%. You are lucky because, in the United States, you can use immunotherapy with pembrolizumab, and you have been able to since 2017, when there was the first FDA agnostic approval of pembrolizumab according to biomarkers regardless of the site of the tumor.

We had to wait until 2021. Very recently, we received EMA [European Medicines Agency] approval of another PD-1 inhibitor, dostarlimab, that we can use as a single agent for patients with MSI-high, recurrent endometrial cancer that has not been heavily pretreated, with no more than 2 previous chemotherapy lines. This is the first time we can use immunotherapy for our patients, so we are experiencing the magnitude of the benefits of immunotherapy when treating MSI-high tumors.

Brad Monk, MD, FACOG, FACS: I am so happy for you. That was February 26th, 2021, according to the press release: “Positive CHMP [Committee for Medicinal Products for Human Use] Opinion for Dostarlimab.” It is a different, but similar checkpoint inhibitor in MSI-high tumors for the European Union. Are you excited about that, Nicoletta, as well?

Nicoletta Colombo, MD, PhD: Yes, yes, I am, because we were far behind. We could not use pembrolizumab, and that was very frustrating. Now we have this opportunity. Thinking of the efficacy of this drug, the toxicity and the profile, and comparing it to chemotherapy, which is quite toxic to this very fragile population—I think is a great opportunity for our patients.

Brad Monk, MD, FACOG, FACS: It is, and I think we all agree, and we are happy for you and for your patients. In the United States, Dave, as Ketta nicely said, since 2017 we’ve had pembrolizumab. Do we need a second checkpoint inhibitor in the United States, or is pembrolizumab enough?

David O’Malley, MD: I am a big fan of competition in the marketplace, and I think it offers our patients options. I think it helps our payers. Ultimately, that is helping our patients. We see, across disease sites, 2 to 3 similar agents that are available. I think, overall, to have the best opportunities for our patients, having a second or a third option is something that I would like to see.

Brad Monk, MD, FACOG, FACS: Are they really different, or is it just a commercial thing and not a scientific thing?

David O’Malley, MD: That is a great question. I think, as we look at checkpoint inhibitors, particularly the PD-1 inhibitors, they are more similar than different. If we look at the single-agent activity, and in those patients with deficiency, it is consistent: 50%, plus or minus 5% to 7%. So the agents we are studying in that deficient population, about 50% plus or minus. As I said, those agents are more likely similar than they are different, but we obviously have never tested them head-to-head to see if there is any significant difference for those patients.

Brad Monk, MD, FACOG, FACS: I think we need to take a broader perspective. This is not the first dostarlimab trial that will ever be done, and so this is the beginning of its life cycle. It is the first step; it is not the end of the story, So I am excited about it too, and I am excited about the ongoing clinical trials, as well as the ongoing clinical trials with pembrolizumab, and durvalumab, and atezolizumab. We will talk about it in a minute.

Domenica (Ketta) Lorusso, MD, PhD: Brad, on top of what David said, I fully support, consider the schedule of treatment. Particularly in a pandemic, the possibility of having a drug that can be administered every 6 weeks and not every 3 weeks could be an opportunity for patients who live very far from the hospital. In general, I support what David and you reported: more options are much better than 1 option in any case.

Brad Monk, MD, FACOG, FACS: I do not know about Europe, but in the US, we can give pembrolizumab every 6 weeks too.

Domenica (Ketta) Lorusso, MD, PhD: Oh, good.

Brad Monk, MD, FACOG, FACS: You can do either; you can do 200 mg every 3 weeks or 400 mg every 6 weeks.

Transcript Edited for Clarity