Let me make sure I've got my lines up correctly and have myself unmuted once you're unmuted. All right, great. No, I had temporarily, I didn't want it to permanently unmute myself, let me get back to the front slide, but thank you very much for allowing me the opportunity to talk with you all today. So yes, really well-timed with that last case. As Dr. Van Lee said, I'm Meredith Newton, I'm one of the GYN Oncology Fellows here at UNC, and I'll share with you on some of the recent updates to our treatment of recurrent and metastatic cervical cancer. So first I'll go over just a brief background on where we stand with our treatment of recurrent and metastatic cervical cancer, and then touch on three updated trials, recent trials in the development, and then briefly hit on some future directions where trials are going. So first, as we know, cervical cancer is a global problem, and it's the fourth most common cancer in women globally, and the third leading cause of cancer-related deaths. And the prognosis for recurrent and metastatic cervical cancer is quite poor with the five-year survival rate of 17%. Typically all these patients recur following first-line therapy, with some of these patients being able to receive second-line therapy about 30 to 70%, but some of these patients are not able to receive second-line therapy as they may die before that point. Now that Bevacizumab has been incorporated into first-line treatment for this group, the options for second-line therapy have generally been single-agent chemotherapies with poor response rates, needing more options for these patients. So first, just touching on kind of the history of where our treatment has been, we historically were using single-agent cisplatin to treat recurrent metastatic cervical cancer. Single-agent cisplatin had demonstrated an objective response rate of 20% with a PFS of 2.8 to 3.2 months, and overall survival of 6.2 to 8 months, which we all know is not a great as your first-line agent. So in 2009, with GEOG204, we investigated cisplatin-based doublet chemotherapy, specifically cisplatin with either Paclitaxel, Topatican, Gemcitabine, or Venerelbine, and they found that there was no great difference between these groups. However, cisplatin, Paclitaxel became the preferred regimen due to the balance of efficacy and toxicity with an improved objective response, PFS, and overall survival compared to single-agent cisplatin. Then in 2014, with GEOG240, we investigated cisplatin-Paclitaxel versus Paclitaxel-Topatican, each doublet with and without Bevacizumab, and with this study, we showed the benefit of the addition of Bevacizumab, regardless of the regimen, improving the overall survival from 13 months to 16.8 months. And so this became the new standard first-line treatment for recurrent metastatic cervical cancer. With this new standard of first-line therapy for second-line, we were then moved to these single-agent chemotherapy agents with, as you can see here, overall objective response rates and PFS and OS that were not very great. So as we have tried to improve our options for second-line treatment, we introduced Pembrolizumab. In Keynote 158, they studied Pembrolizumab for recurrent metastatic cervical cancer in the second-line treatment, and from this study, we had approval for use in PD-L1 positive tumors, and for PD-L1 positive tumors, this study showed an objective response rate of 14.6%, a PFS of 2.1 months, and an overall survival of 11 months, and none of the PD-L1 negative patients responded. But one of the limitations of this study was that the histologies were limited predominantly to squamous carcinomas with 94%. So following Keynote 158, we now have Keynote 826 that was published this year, and in Keynote 826, it was a randomized controlled trial of Pembrolizumab versus placebo in addition to platinum-based doublet chemotherapy plus or minus Bevacizumab in the first-line treatment. The results were included if they had persistent, recurrent, or metastatic cervical cancer with either squamous, adeno, or adenosquamous histologies, and patients were randomized to either placebo every three weeks or Pembro 200 milligrams every three weeks in addition to Paclitaxel and investigator-choice cisplatin or carboplatin, and then with the addition of Bev if eligible. The primary outcome of the study was the overall survival and progression-free survival. So of note in Table 1 characteristics, there weren't any major differences, but they were able to include a more diverse inclusion of histologies with 18% adenocarcinoma in the control group and 27% in the, or vice versa, sorry, 18% in the Pembro group and 27% in the placebo group. They also had representation of about 11% in each group of PD-L1 less than one on a CPS score, and about 63% in each group did receive Bevacizumab with their first-line therapy. So in terms of their primary outcomes, on the left is progression-free survival and on the right is overall survival, and you can see that there was an improvement in both of these outcomes with the use of Pembrolizumab, and then in terms of their subgroup analyses, I've highlighted here the PD-L1 CPS score, and you can note that when the score was less than one, their confidence interval and hazard ratio crossed one. So the conclusion of this trial was that the addition of Pembro to the standard first-line treatment of recurrent metastatic cervical cancer reduced the hazard of disease and disease progression and hazard of death, and as I just pointed out in the subgroup analysis, the PD-L1 CPS score less than one group had a hazard ratio with a confidence interval crossed one, but the authors of this paper suggested that because this was a small group, it was not possible to draw clear conclusions, but the effect, if any, was small. And in terms of adverse events, there were no new safety signals, and so in conclusion, this study found that the PFS and overall survival were significantly longer with the addition of Pembro to platinum-based chemo with or without Bevacizumab in the first-line treatment of patients. So now we have keynote promoting Pembro in the first-line treatment, and then to improve our additional second-line options, we have the ANOVA TV-204 trial. So first, just touching on Tizotimab, it is an antibody drug conjugate that is directed against tissue factor. Tissue factor is prevalent in multiple solid tumors, including cervical cancer. TV is conjugated to the microtubule disrupting agent monomethyl erstatin E, also known as MMAE. So on the image here, you can see that TV is here in the upper left-hand corner with MMAE represented by these red dots. When TV binds to tissue factor, it is internalized into the cell, and MMAE is released, and this leads to direct cytotoxicity by cell cycle arrest and apoptosis, and also induces bystander killing by release of the MMAE, along with some other processes. This trial was a phase two trial for use of TV in the second line of treatment for recurrent metastatic cervical cancer. Patients were included, again, if they had adeno, adenosquamous, or squamous cell cancer after progression of first-line treatment. Patients in the study were given two milligrams per kilogram every three weeks until progression or unacceptable toxicity, and their primary outcome was the objective response rate. Of note, all patients were assessed by an ophthalmologist at baseline and with each cycle and referred for any symptoms or findings. A strict mitigation strategy was employed to reduce ocular adverse events. So here you can see some of the instructions that were utilized for this mitigation strategy and the use of multiple agents, vasoconstrictor drops, corticosteroid drops, cold ice packs to the eyes, and lubricating drops, in order to reduce the ocular adverse events. In the table one characteristics of this study, again, we can see a little bit broader representation of histologies, as well as about 63 to 69 percent of patients received prior bevacizumab, and most of these patients had tissue factor expression of their tumors. So based on their outcomes that they sought, they had a 24 percent objective response rate, 8.3 months was the median duration of response, 4.2 months was the median progression-free survival, and 12.1 months was the median overall survival. On the right, the objective response rate of the overall population is represented by the dotted line with each individual subgroup analysis represented along this dotted line, and globally speaking, what you can see here is that all these subgroup analyses were represented in their confidence interval with the population, and so none of these subgroups seem to have any major differences beyond the overall population results. T.V. had three adverse events of special interest, ocular adverse events, bleeding, and peripheral neuropathy, and this was because peripheral neuropathy is a known side effect of MMAEs. Bleeding was of special interest due to tissue factors, part in coagulation pathway, as well as its expression on the nasal epithelium, and the mechanism of action of ocular events is not known, but tissue factor has been demonstrated in the ocular epithelium. On the left here, you can see the representation by grade 1, grade 2, and grade 3 events. The most common ocular events were conjunctivitis, dry eye, and keratitis. The most common bleeding events were epistaxis, and the most common neuropathy events were peripheral neuropathy, peripheral sensor neuropathy. On the right, you can see the time to onset of these events, the percent of events that resolve by the 30-day follow-up, and the time to onset of these events. The time to resolution was earlier onset of ocular and bleeding events. Most ocular and bleeding events resolved, and the lower resolution of peripheral neuropathy may be more dictated by the duration of this follow-up period being short. So, in conclusion, this study found an objective response rate of 24 percent that was better than other options that have been available with second-line treatment and a longer duration of response. They also remarked on the quick time to response of 1.4 months may be important for this population that may have rapid progression. The strength of the study was that most patients received BEV, which is up-to-date to current treatments. Also, the response to TV did not appear to be impacted by BEV, based on the subgroup analyses. Also, based on the subgroup analyses, all histologies seemed to have equal response, and there was no clear association between tissue factor levels and response. So, now we have FDA approval for TV for recurrent metastatic cervical cancer in the second-line treatment. And finally, just hitting briefly on the EMPOWER Cervical 1 study, which I know I think you briefly touched on last month. So, the EMPOWER Cervical 1 study was a randomized controlled trial of simiplimab for investigators' choice in the second-line treatment of recurrent metastatic cervical cancer. Simiplimab is a PD-1 receptor monoclonal antibody, and it is currently approved in some other cancers. Patients were included if they had recurrent metastatic cervical cancer that had progressed after first-line therapy. Again, they could have squamous adeno or adenosquamous histologies, and patients were enrolled regardless of the PD-L1 expression. Patients were randomized to either investigators' choice single-agent chemotherapy or simiplimab 350 milligrams every three weeks, and the primary outcome was overall survival. So, here you can see the overall…the Kaplan-Meier curve for the overall population, the squamous cell population, the adenocarcinoma population, with all three groups seeing a survival benefit with simiplimab. Then, when broken down by PD-L1, the group that received simiplimab with a PD-L1 expression less than 1% had an equal survival to the chemotherapy group. So, this study concluded that from this randomized controlled trial, simiplimab is the first immunotherapy to demonstrate statistically significant and clinically meaningful survival benefit over chemotherapy for recurrent and metastatic cervical cancer following progression after first-line platinum-based therapy. In the overall population, they showed an overall survival benefit. The authors also noted a numerical overall survival benefit of simiplimab in the PD-L1 less than 1% group, but the largest benefit of no surprise was to the PD-L1 expression greater than or equal to 1%. The quality-of-life assessments favored simiplimab, and there were no new safety signals identified. So, now, simiplimab is seeking approval for use in the second-line therapy, and they are hoping to expand the use of checkpoint inhibitors to all patients regardless of PD-L1 status. In terms of briefly hitting on future directions, KinoA18 is a phase 3 trial looking to use Pembro with adjuvant chemoradiation for high-risk locally advanced cervical cancer. This is clearly a different group than one we've been discussing, but using Pembro in other groups of treatment. In the ANOVA-TV trial, it's a phase 1B2 study using TV in combination with either Pembro, Carbo, or Bev for recurrent metastatic cervical cancer. Some of these arms are first-line, and some are for second-line treatment. And the last trial is a phase 3 trial of TV versus investigator's choice for second-line treatment for recurrent metastatic cervical cancer, so some things to look out on the horizon for. And then I leave this here as a question of does this lead to our – is this our new treatment paradigm, assessing PD-L1 status, utilizing Pembro in the first line, moving towards to Zotimab, maybe Simlipimab in the second line, and then leaning on our single-agent chemotherapies as third-line? Thank you for the opportunity to discuss today.

cervical cancer

recurrent

metastatic

chemotherapy

immunotherapy