I didn't know the cases ahead of time, but this fits really well. I think both of the cases we talked about today would have actually been eligible for this trial. Just as some brief background, cervical cancer is the fourth most common cancer in women worldwide with over 660,000 new cases and 350,000 deaths globally per year. These heat maps show the cervical cancer incidence and death rates, so you can see the highest burden of diseases in Sub-Saharan Africa, Central America, and then parts of Southeast Asia. Vietnam last year, or two years ago, rather, had 4,600 new cases and about 2,500 deaths. And per capita, it looks, based on the heat map, pretty similar to the United States. So the standard of care for locally advanced cervical cancer is external beam radiotherapy with concurrent chemotherapy, typically cisplatin, followed by brachytherapy. And this standard of care has been in place for over 20 years. So below are some of the key survival curves from the landmark trials that established this standard. So RTOG9009 was for locally advanced cervical cancer with or without positive pelvic nodes. Patients were randomized to extended field radiotherapy versus chemo radiation, and there was an overall survival benefit with addition of chemo. And then GOG123, this evaluated bulky 1B disease. Patients were randomized to radiotherapy versus cis-RT, and all of these patients also had adjuvant hysterectomy, but you can see there was an overall survival benefit to cis-RT. And then finally, GOG120 in the bottom right, also for locally advanced cervical cancer. In this study, patients were randomized to three different chemo regimens alongside EBRT, and the cisplatin-containing regimens had the best survival. And there didn't appear to be any additional benefit with fluorouracil and hydroxyurea. As you can see, those two curves follow pretty closely with each other. So, despite curative intent cis-RT, five-year overall survival for locally advanced cervical cancer remains fairly poor. It's estimated at about 50 to 80% five-year survival, and of course, those with more advanced disease fare worse with it closer to the 50% mark. So, there remains an unmet need in treating this group of patients. So, in recent years, Pembrolizumab has shown an overall survival benefit as monotherapy, or combined with chemotherapy with or without Bevacizumab in the treatment of recurrent, persistent, or metastatic cervical cancer. So, the aim of Keynote 18 was to evaluate the addition of Pembrolizumab instead in the upfront setting for high-risk, locally advanced disease. So, this study evaluated Pembrolizumab versus placebo given alongside Chemo-RT, followed by maintenance Pembrolizumab or placebo, and this was a randomized, double-blind, placebo-controlled phase three trial. So, the study included FIGO 2014, stage 1b2 to 2b node-positive disease, or stage 3 to 4b to 2b node-positive disease, or stage 3 to 4a, regardless of nodal status, and all patients were newly diagnosed, treatment naive, and it included squamous cell and adenocarcinoma histologies. Patients were randomized one-to-one to receive standard of care, so pelvic RT with weekly cisplatin, followed by brachytherapy versus the standard of care, plus Pembrolizumab upfront with the cis-RT, and then followed by maintenance Pembrolizumab for about two years. And patients were stratified prior to randomization according to type of EBRT, total RT dose, and stage, and then we'll focus on the primary endpoints, PFS and OS. The study recruited from 176 sites in 30 countries, so it was truly a global study, and about 530 patients were randomized to each arm. These charts show the baseline characteristics of the intention-to-treat population, so patients were generally well-balanced with respect to demographics, disease characteristics, and histology, and lymph node involvement, and notably, over 90% of the patients received modern IMRT techniques, and about 95% were PD-L1 positive. So these Kaplan-Meier curves show the PFS at the first and second interim analysis for the study. At 36 months, on the right-hand side of the screen, 29% in the PEMBR arm, and 40% in the placebo arm had experienced progression, and the hazard ratio for PFS was 0.68, which was statistically significant and showed a benefit of PEMBRO. Following the first interim analysis, which is displayed on the left-hand side, in the U.S., the FDA approved this regimen for stage III to IV-A, but not I.B. to II.B. node-positive disease. As the PFS improvement in the overall population, when they subdivided the patients into stage, the benefit in the overall population seemed to be attributable to the advanced-stage disease. At both of the interim analysis, the PFS hazard ratio in the earlier-stage disease showed a trend towards benefit, but neither was significant. And this shows the Kaplan-Meier curve for overall survival. So at 36 months, the overall survival was 83% in the PEMBRO arm compared to 75% in the placebo arm, and there was a significant overall survival benefit with a hazard ratio of 0.67 in the overall intention-to-treat population. The hazard ratio for death was less than one in all subgroups of patients, which you can see on the right-hand side, except for those over 65 and those with PD-L1-negative disease. And these were both fairly small groups. Those under 65 made up about 12% of the population, and then only 5% of the study population was PD-L1-negative. And then just briefly, we can go over the secondary endpoints. Overall, the response rate was slightly higher in the intervention arm by about four percentage points. So I think not really surprising since the standard of care does have a reliably good response rate. It's just the problem is remaining relapse-free. And then the duration of response also heavily favored the intervention arm. I think also not, excuse me, particularly surprising since the intervention arm was receiving maintenance therapy throughout follow-up. And then I won't go over all of the adverse event and safety data, but the key points from this slide is that there was a higher rate of AEs or adverse events in those who got PEMBRO, but these toxicities were generally expected and were overall acceptable in the context of the survival benefit that was seen. The great majority, over 95% of the immune-related adverse events attributable to PEMBRO were grades one and two, so fairly minor. And then there was the same number of treatment-related deaths in both arms. So there were two treatment-related deaths in both arms. Excuse me. And only one was directly attributable to PEMBROlizumab. One patient had immune-related gastritis. So in conclusion, PEMBROlizumab combined with chemoradiotherapy and then continued as maintenance therapy improves progression-free and overall survival. Toxicities were manageable and overall acceptable. And together, these data support PEMBRO plus chemoradiotherapy as the new standard of care in high-risk, locally advanced cervical cancer. Briefly, some strengths of the study is it was a large study with over 1,000 patients, which allowed it to be powered to evaluate overall survival. There was good quality assurance across sites of radiotherapy techniques, so we can have more trust that the difference between the groups was due to the intervention and not differences in radiation techniques. And there was good geographic diversity with over 30 countries represented. And then some limitations are it uses FIGO 2014 staging, so it can be a little bit more ambiguous or confusing when we try to apply it to our patients using current staging. And then there was a low enrollment of black women, so we may have some trouble generalizing it to all groups. And then lastly, how do we interpret this study in the setting of two other major studies, recent phase three global trials, including locally advanced cervical cancer? So the CALA study is in the middle column. So this was published in 2023. And the study was very similar to A18 in that it was evaluating an immune checkpoint inhibitor and it added to chemoradiotherapy or chemoradiation. The study used Dervalimab, which is a PD-L1 inhibitor rather than Pembrolizumab, which is a PD-1 inhibitor. And this was a negative study failing to show a significant improvement in PFS. One key difference between these two studies is the, or between CALA and Keynode 18 is the definition of lymph node positivity, which affects the inclusion criteria. So CALA had a lower threshold for inclusion. They required just one or more lymph node, one centimeter or more in the short axis, whereas Keynode 18 required two or more lymph nodes and they had to be 1.5 centimeters or greater in the shorter axis. So overall, this made CALA's patient population a lower risk population. So it may have been more difficult to show a benefit of the intervention. In other words, some of the patients may have been, with lower risk disease, may have been adequately treated with the current standard of care. So the effect of the intervention was kind of, may have been diluted in that sense. And then another difference was the mechanism of action of the drug as a PD-1 versus a PD-L1 inhibitor. So Pembroaxon T-cells and Dervalamab axon, the tumor itself, so the tumor microenvironment may have been another variable in the CALA study that may not have been as present in A18. And then Interlace, which I understand you guys talked about last time, was published in 2024 and evaluated addition of induction chemo prior to the standard of care chemoradiation. And they found a significant PFS and OS benefit with induction chemo. So I think cross-trial comparison with Keynode 18 and Interlace is virtually impossible since the interventions were completely different and the duration of follow-up available is also a bit different with more follow-up available for Interlace. But I think one notable difference is that Interlace was applicable to a broader locally advanced cervical cancer population. So they included 1B1 disease with positive lymph nodes as well as 1B2 to stage two disease, regardless of lymph node status, whereas Keynode 18 didn't include any 1B1 regardless of lymph node status. And then if there were 1B2 or 2B, they had to have positive lymph nodes. So more patients would qualify for Interlace with locally advanced cervical cancer. But I think it is tricky if a patient meets criteria for both deciding which to do. And I think if that's the case, it may be more of a question of like drug availability and resources on hand. Interlace protocol may be more helpful in more resource constrained settings. For example, if access to Pembrolizumab is limited or cost prohibitive, or if patients are, if access to radiotherapy is more limited and patients would have to wait to get radiation, it may make them more suitable to Interlace because then you could go ahead and start induction chemo in that meantime. And those are my sources and that's all I got. So thanks so much for your attention and thanks for having me tonight.

Pembrolizumab

cervical cancer

chemoradiotherapy

progression-free survival

global data