Can you guys see my slides? Okay. Looks good. I'm going to try to make this short. We'll see how quickly I can talk through this. But thanks for, thank you for inviting me today. So I'm going to talk about immunotherapy and gynecologic malignancies. So a little bit of immunotherapy and cervix endometrial as well. So quickly summarize that this figure represents estimated deaths in the United States. And there is an increasing mortality rate among uterine cancer patients. It's one of the only cancer types that's increasing in mortality and it's approaching that of ovarian cancer. And the figure on the right side, it's the only cancer that has a subset, a sub insert to show that there's an increasing mortality rate. So it's pretty alarming of all the cancer types in the body. It's only the second highest of increasing mortality rate. In addition to that, cervical cancer remains the most common malignancy worldwide with over 300,000 deaths annually. And with the rising incidence of some gynecologic cancers and corresponding mortality rates, there is an inference that maybe we've met our plateau with chemotherapy and there's a need for more innovative treatment options. And one of those is immunotherapy. When we talk about immunotherapy, it's not only checkpoint inhibition, but my talk will be focused on checkpoint inhibition. Immunotherapy includes CAR T cells that increases the quality and quantity of effector immune cells, the use of vaccines by introducing tumor antigens into the immune system. And then finally, checkpoint inhibition that I'll go a little further into, which neutralizes the innate or acquired immunosuppressive mechanisms. So checkpoint inhibition works through two axes. So this is the most basic of science slide I have, but it either works through the CTLA-4 axis or the PD-1 PD-L1 axis. When a T cell recognizes antigen in the lymph nodes, so this is a central pathway, CTLA-4 acts as a negative regulator, meaning it kind of pumps the brakes on immune activation. Similarly, in peripheral tissues, the PD-1 PD-L1 axis can turn off anti-tumor T cell responses. So blocking either PD-1 or PD-L1 allows antigen presenting cells to activate a T cell response and then recognize and kill cancer cells. And you can imagine because the CTLA-4 axis is centrally in lymph nodes that those targeted drugs might have more side effects. Immunotherapy has been around for a while. This is even an outdated slide, but I just wanted to include it to show that immunotherapy has been around for over 20 years. It's well-studied in other malignancies like melanoma and GU malignancies, and it was the breakthrough of the year in 2000. And so it's relatively new to gynecologic malignancies, but it's well-studied in other cancer types. And because it's been studied in other cancer types, we have long-term survival data for some of those. Melanoma was the first cancer where immunotherapy was implemented, and our long-term survival data from melanoma studies show that the pre-immunotherapy era, overall survival rate was only 10%, and now that's increased to almost 50. And similarly, in lung and kidney carcinomas, there's an improvement at five and three and a half year overall survival. So it's really promising, and we have new indications in gynecologic malignancies that are really exciting. But first, I'm going to start with ovary and vulvar, which are not as exciting, just to get those out of the way. But the evidence we have in ovary is somewhat disappointing. Single-agent pimpolizumab only had an 8% objective response rate in recurrent ovarian cancer. It is not better than upfront chemotherapy. We do employ it in the platinum-resistant setting with cytoxan and avastin. And vulvar carcinoma, it's not so much that we just don't know because it's a rare cancer. It's included in keynote 158. Only a small number of tumors were included, and in vulvar malignancies, IO only had an 11% response rate. Where we see more exciting progress with immunotherapies in endometrial and cervical cancers. So in endometrial cancers, it's been approved in both MMR-deficient and MMR-proficient tumors. And cervical tumors, initially with CPS-positive, but recently with AA18, it's been approved in the upfront setting in locally advanced cancers, and then was previously approved in metastatic and recurrent combined with chemotherapy. So I won't go through all of these in too much detail, but this is the approval of immunotherapy in gynecologic malignancies since 2018. We now have three approvals in cervical cancer and four approvals in endometrial cancer. And I'll go through the hallmark trials real quick that led to these approvals. So first, in endometrial cancer, we have keynote 775. This was a phase three clinical trial of endometrial cancers who progressed on platinum-based chemotherapy, and the treatment arms were pembrolizumab plus lingbima versus standard of care, which was a doxil or a paclitaxel. What they found was that patients who had combination pembrolizumab and lingbima had an objective response rate of 30% versus standard of care of only 15%, so a doubling on objective response rate, which was great, and an improvement of almost five months in overall survival and a duration of response of four months. So this was a big finding, and it led to pembrolizumab and lingbima being the second line therapy in advanced and recurrent endometrial cancer. And then in 2022, it's two big studies, RUBY and GYO1AIDS. This is RUBY, which was a phase three study of stage three and four and recurrent endometrial cancers. This also included carcinosarcoma, so that's one of the only studies that has carcinosarcomas included. The two arms were chemo plus distalimab plus maintenance versus chemo and placebo, and distalimab improved PFS at two years, significantly in the MMR-deficient arm from 15% to 61%, and additionally in all comers as well. OS improved from 56% to 71% as well. In similar findings in GYO1AIDS, this is the addition of pembrolizumab with chemotherapy in advanced and recurrent endometrial carcinomas, also with maintenance. We won't have overall survival data in this analysis, but they did see a PFS benefit in the MMR-deficient arm and the MMR-proficient arm. Okay, finally, cervical cancer. So cervical cancer was one of the first cancer gynecologic malignancies where immunotherapy was approved, and it's an emerging treatment option in combination with radiation and other targeted treatments in cervical cancer, so I think that as we learn more about immunotherapy, we'll continue to implement it into our standard of care. The hallmark trials for cervical cancer that led to approval in the recurrent and metastatic settings include Keynote 158. This was a phase two study that delivered immunotherapy to cervical cancer patients that were heavily pretreated. Most of those had PD-L1-positive tumors. The objective response rate was 15% to 20%, and of those that responded, they were all PD-L1-positive tumors. And then additionally, Keynote 826 led to the approval of immunotherapy in advanced and recurrent setting in combination with Carbotexel Bev. The addition of pembrolizumab improved OS and PFS, and specifically, OS at two years improved from 41% to 53%. And then among all the cohorts, those that did not respond had a PD-L1 CPS score less than one, so this was just a small subset of patients, but in the initial approvals of immunotherapy in cervical cancer, the indication did include a CPS score greater than one. And then finally, this is the most recent cervical IO study from the fall of 2024, so this is Keynote A118. This included patients with 1B2 or 2B disease that had positive lymph nodes and who were stage 3 and 4A based on FIGO 2014 staging. Patients were triaged either to chemo RT, which is standard of care, versus receiving additional pembrolizumab with chemo RT, and then 15 cycles of pembro maintenance. They did not stratify patients by CPS score, and pembrolizumab has been approved regardless of CPS score in this population. And the addition of pembrolizumab and maintenance improved overall survival from 75% to 83% at 36 months. Okay, going forward, I think we have really exciting studies in endometrial cervix, and we have to do a little bit more digging how to figure out how, if immunotherapy will ever work in ovarian cancer, but it's certainly a hot topic, and maybe we'll figure it out one day. But of the trials that are in development, it's investigating whether immunotherapy works with our current standard of care treatments and how we can better optimize immunotherapy. So this is a summary of current trials. Some of them have resulted, like A18 is on this list. So lots going on with immunotherapy and a lot to look forward to and how we can incorporate it with our patients. Okay, thank you. Thanks for your time and your attention.

immunotherapy

gynecologic cancers

checkpoint inhibition

Keynote trials

innovative treatments