KEYNOTE-826 Data Confirm Survival Benefit of Pembrolizumab Addition in Cervical Cancer

The addition of pembrolizumab (Keytruda) to chemotherapy with or without bevacizumab (Avastin) for the first-line treatment of patients with persistent, recurrent, or metastatic cervical cancer continues to demonstrate significant survival benefits, according to updated findings from the phase 3 KEYNOTE-826 trial (NCT03635567).

After a median follow-up of over 3 years (39.1 months), the addition of pembrolizumab led to an overall survival (OS) of 28.6 months vs 16.5 months in the placebo group for those with a PD-L1 combined positive score of 1 or higher. For patients with a PD-L1 combined positive score of 10 or higher, the OS rates were 29.6 months vs 17.4 months, and for all patients, the OS was 26.4 months vs 16.8 months with the addition of pembrolizumab vs placebo. A clinical benefit was also observed regarding progression-free survival (PFS). In the pembrolizumab group, PFS was 10.4 months vs 8.2 months with placebo for all participants.

Additionally, these updates findings showed that treatment with pembrolizumab plus chemotherapy reduced the risk of death by 40% in patients with a PD-L1 combined positive score of 1 or higher, by 42% in patients with a PD-L1 combined positive score of 10 or higher, and by 37% in all patients, and there were no new safety findings reported after more than 3 years of follow-up.

“This is now recommended and preferred. That's what community oncologists, academic oncologists, and patients, advocates, and survivors need to know, and this is the way you treat metastatic recurrent or persistent cervical cancer today.” said Bradley J. Monk, MD, FACOG, FACS, in an interview with Targeted Oncology^TM.

In the interview, Monk, Bradley J. Monk, MD, FACS, FACOG, professor, division of gynecologic oncology, University of Arizona College of Medicine, Creighton University School of Medicine, director, principal investigator, community research development, HonorHealth Research Institute, vice president and member board of directors GOG-Foundation, co-director GOG-partners, highlighted final results from the phase 3 KEYNOTE-826 trial of pembrolizumab plus chemotherapy vs chemotherapy plus placebo, with or without bevacizumab in persistent, recurrent, or metastatic cervical cancer.

Targeted Oncology: Could you explain the rationale behind the KEYNOTE-826 study?

Monk: Virtually all cervical cancers are caused by the human papilloma virus, what we call HPV. We developed a vaccine in 2006, which is almost 100% effective in preventing this infection, and we can test for the virus on the cervix and determine a woman's risk. But that's not happening. And because that's not happening, cervical cancer is the fourth most common cause of cancer related deaths worldwide. There are more than 4000 deaths in the [United States] every year, and there has been a plateau for more than 20 years. I have to say that because this is a preventable cancer. Because we are not achieving our goals, we need to find better treatments for women whose cervical cancer is life threatening. Those are really 3 categories. Those are categories who get chemotherapy and radiation, and it doesn't go away. It's also women whose cancers come back, recurrent, and then thirdly, it's women who have de novo widely metastatic disease stage IV.

Because this is a virally induced cancer, it should be susceptible to immunotherapy, immunotherapy with an immune checkpoint inhibitor, immunotherapy with pembrolizumab, which is a humanized monoclonal antibody against PD-L1. In fact, we had preliminary data only on 77 patients with a response rate of only 14.3%, which led to the FDA approval in June of 2018. Now, although responses were rare, they were durable, and it was tolerable. We committed to do a confirmatory trial, and that accelerated approval was in the second-line. We committed to a randomized phase 3 trial in the first-line, persistent recurrent stage IV setting, adding it to available therapy to see if we can help women live longer and live better. That study is called KEYNOTE-826. Based on a preliminary result with follow-up of less than 2 years, it got FDA approval on October 13, 2021, so [it was an] accelerated approval.

Can you discuss the mature results from KEYNOTE-826?

At the time of the interim analysis, follow-up was less than 2 years, and the medians had not been met. Statistically, the hazard ratio was 0.64, and that's why it got FDA-approved. The therapy that pembrolizumab was added to was platinum and taxane-based chemotherapy with and without bevacizumab. Bevacizumab was approved in 2014 and we have had nothing since. When pembrolizumab is added to chemotherapy with or without bevacizumab, women, who are on average around 48-50 years of age, live a year longer. These are young women who now are living longer because of research that was done by the investigators and by patients and their families who contributed, and a sponsor who makes pembrolizumab. This is a transformational result. This is not changing a CAT scan, what we call progression-free survival. This is changing a woman's life. The more intensive therapy helps her live 12.1 months longer with a hazard ratio of 0.60 and doesn't decay her quality-of-life.

We published in April of 2023 in the Lancet Oncology that there was no decrease in patient reported outcomes or quality-of-life. In fact, there were numerical increases in quality-of-life. Patients are living longer and they're living better. That is the definition of clinical trials. That's why we as investigators get up in the morning. At a time, maybe 20 years ago, where we had no treatment for women with persistent recurrent or stage IVB cervical cancer, we developed chemotherapy, we added bevacizumab to it, and now we have quadruplet therapy where women on average can live 28.6 months, which means that 50% live longer.

For community oncologists, what would you say are the key takeaways from this trial?

One of the key takeaways from KEYNOTE-826 that was presented at ASCO 2023 is that people don't really know that pembrolizumab can be added to chemotherapy with or without bevacizumab to help women live longer. Cervical cancer, fortunately, is rare. But in Arizona, it's a serious health burden. It's serious everywhere, but not only is it serious in Arizona, it's common, particularly in the Latino population. Community oncologists need to know that this is available. Again, platinum taxane and then bevacizumab was approved in 2014. Then in 2021, 7 years later, we added pembrolizumab to it in the frontline. Now we have mature results, not only in the clinical outcomes, but in the patient reported outcomes. Community oncologists need to know that this is now the new standard of care. This is now NCCN recommended and preferred. That's what community oncologists, academic oncologists, and patients, advocates, and survivors need to know, and this is the way to treat metastatic recurrent or persistent cervical cancer today.

Moving forward, what unmet needs must be addressed?

The biggest unmet need in cervical cancer is that we could prevent it. That obviously is the best approach, but it's not happening to the degree that is satisfactory. The biggest unmet medical need in recurrent or persistent cervical cancer is that we're not curing enough patients. It's possible and probable, in fact, there's a tail on the KEYNOTE-826 curves that there are patients with metastatic cancer that are cured, but we can do better. We cannot ever leave a woman behind with recurrent, metastatic, or persistent cervical cancer. That's the unmet need. What that is will be a dual checkpoint inhibitor, so blockade with a PD-1/PD-L1 plus to CTLA4, it will be antibody drug conjugates, and it will be better surgical and better radiation techniques. We still have a lot to do.

Are there any ongoing trials that are exciting in the space?

One of the most exciting trials that I hope to see very soon is taking the results of KEYNOTE-826 that were presented at ASCO 2023, where pembrolizumab was added in the first-line to chemotherapy with/without bevacizumab, and now trying to add it to chemotherapy and radiation at the very onset of intervention. Why would we do that? Because it's approved in the first-line metastatic setting, and we want to cure more patients. That study is called KEYNOTE-A18 [NCT04221945], and we're excited to see that result, hopefully soon.

Then, 1 of the most exciting areas of research in gynecologic oncology, like other solid and liquid tumors, is antibody drug conjugates. For the first time ever, we [can] show that an antibody drug conjugate can help patients with platinum-resistant recurrent ovarian cancer live longer, and that medication is mirvetuximab soravtansine [Elahere], and that study is called MIRASOL [NCT04209855]. That is the first time that we have ever seen a medication help women live longer vs physicians choosing chemotherapy in platinum-resistant, recurrent ovarian cancer. The safety profile was better than the physician's choice of chemotherapy. Again, accomplishing our goals as investigators and clinicians to help patients live longer and live better.

Monk BJ, Colombo N, Tewari KS, et al. KEYNOTE-826: Final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer. J Clin Oncol. 2023;41(suppl 16):5500. doi:10.1200/JCO.2023.41.16_suppl.5500