Revolutionizing Frontline Cervical Cancer Treatment: Trials to Transformative Therapies

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An overview of the remarkable evolution in the treatment landscape for metastatic and recurrent cervical cancer patients, shaped by pivotal clinical trials and the integration of immunotherapy, resulting in significantly improved clinical outcomes.

Transcript:

Ramez N. Eskander, MD: There has been a significant improvement in clinical outcomes based on our identification of effective systemic therapy in the [patient with] newly diagnosed metastatic cervical cancer or in the [patient with] recurrent treatment-naïve cervical cancer. And that evolution has been a result of many clinical trials. We had firstly, GOG [Gynecologic Oncology Group] protocol 204, which was a trial that looked at a cisplatin-based chemotherapy doublet. And from that trial, cisplatin and paclitaxel emerged as a preferred chemotherapy combination. That was published by Dr Monk and colleagues in JCO [Journal of Clinical Oncology] in 2018. Following that, we had the second subsequent trial to inform treatment, and that was GOG protocol 240, which was led by Dr Tewari.

GOG protocol 240 was a 4-arm trial, and it looked to determine whether there was going to be a benefit with the addition of bevacizumab to the chemotherapy backbone. Why? Because angiogenesis was a hallmark of cervical carcinoma, and that was discovered based on prior translational research and investigation, but also based on phase 2 studies showing efficacy of bevacizumab as a monotherapy. GOG 240 also wanted to [answer] the question [of whether] a nonplatinum doublet could improve outcomes. So it was a 2-by-2 factorial design: chemotherapy with or without bevacizumab. And then for the chemotherapy backbone, it was a platinum-based doublet or topotecan paclitaxel, which was a nonplatinum component.

And what we saw from GOG 240 was a significant improvement in the median overall survival with the addition of bevacizumab to chemotherapy. It went from 13.3 months to 17 months. That’s a dramatic improvement, and the median progression-free survival went from 5.9 months to 8.2 months. We had a significant improvement in progression-free survival and a significant improvement in overall survival with the addition of bevacizumab to chemotherapy. The nonplatinum doublet combination did not inform a change in practice. So GOG 240 established chemotherapy, cisplatin or carboplatin, plus paclitaxel plus bevacizumab as our treatment backbone for patients with metastatic or advanced-stage cervical carcinoma.

And then we evolved to … an era of immunotherapy. Why? Because we knew from the KEYNOTE-158 trial that patients who have cervical carcinoma [and] are PD-L1 positive by a combined positive score [CPS] responded to pembrolizumab. And if they responded, the median duration of response was not reached. So, of course, it became a rational next step to determine whether using pembrolizumab in these patients could improve clinical outcomes. So that was KEYNOTE-826. It was a phase 3 trial that looked at chemotherapy with pembrolizumab and pembrolizumab maintenance or chemotherapy placebo [and] placebo maintenance. And bevacizumab was at the physician’s discretion. That’s key because KEYNOTE-826 was not a trial that was designed to ask or answer a question about bevacizumab plus immunotherapy, but rather, it was really focused on the benefit of pembrolizumab, with bevacizumab being physician’s choice.

And because of that, it was a stratification factor. You had to know whether you’re going to give [bevacizumab] and whether you plan to use it. And thankfully, as was initially published by Dr Nicoletta Colombo, but of course updated by Dr Brad Monk at ASCO [American Society of Clinical Oncology Annual Meeting] in 2023, KEYNOTE-826 met its primary end points with a significant improvement in progression-free survival and overall survival in these patient populations. But an important caveat to that is that they looked at various CPS categories: PD-L1 CPS of 0, 1 to 10, and greater than 10. In the intent-to-treat population, it was positive in the 1 or greater population [and] it was positive in the greater than 10 population.…

So we saw a benefit across the board. Importantly, nearly 90% of patients were PD-L1 CPS 1 or greater; it was the vast majority of those enrolled. And that’s very important as we look to connect this to the clinical patients we care for…. If you look at the intent-to-treat population, the median overall survival was greater than 24 months, really dramatically changing how we treat these [patients with] advanced-stage cervical cancer. [It’s about] bringing this combination of platinum, paclitaxel, [and] pembrolizumab with or without bevacizumab as the preferred systemic chemotherapy strategy for [a patient with] metastatic or recurrent cervical cancer who is treatment naïve, who has a CPS in PD-L1 of 1 or greater. If they have a CPS of 0, then that doesn’t fall within the label. And those patients, of course, would have the GOG 240 [regimen] of platinum, paclitaxel, bevacizumab, and bevacizumab maintenance.

…We’ve seen overall survival transform. And why? As I mentioned earlier, in GOG 204, the median overall survival was [approximately] 12 months. GOG 240 took median overall survival for these patients to 17 months. And then KEYNOTE-826 took that to almost 26 months. So you’re seeing this really dramatic improvement in overall survival for patients who had a very guarded prognosis a decade ago. It’s dramatic, it’s exciting, and, most importantly, it gives our patients options.

Transcript is AI generated and edited for readability.

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