Addition of Pembrolizumab to Chemotherapy Can Significantly Improve Survival Outcomes in Patients with Cervical Cancer

Bradley J. Monk, MD, Division of Gynecological Oncology, HonorHealth Research Institute, University of Arizona College of Medicine, Phoenix, and Creighton University School of Medicine discusses KEYNOTE-826, which identified pembrolizumab(Keytruda; Merck) as an effective immunotherapeutic agent for woman with cervical cancer at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, from June 2 to 6.

PT Staff: What are pembrolizumab’s primary mechanisms of action?

Bradley J. Monk, MD: So cervical cancer is the fourth most common cause of cancer related death in women worldwide. And even in the United States, there are more than 4,000 deaths. How is that possible? How is that possible when the virus that causes cervical cancer, the human papilloma virus (sometimes called HPV) can be prevented through vaccination? When people are not being vaccinated—even though the vaccine has been around since 2006. Even if you don't get vaccinated, you can go to your doctor and you can check for the virus right on the cervix and get a viral test. If you're not vaccinated, sound familiar? And if the virus is there, you can sort of go through some tests and make sure that you're not going to have a serious complication from cervical cancer. Women are not doing that either.

So we are here now today to talk about what happens when cervical cancer doesn't go away with chemotherapy and radiation; It’s called persistent. [Persistent is] When cervical cancer gets cut out— or receives chemotherapy and radiation— and recurs, or when it's found de novo stage 4. And we lump that into the first line. We call those 3 buckets first-line treatment. We don't count chemotherapy and radiation as a line of therapy. Standard treatment in 2009 became chemotherapy. And then we waited for 5 years and bevacizumab (Avastin; Genentech), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Bevacizumab was added to it, and we increase the survival from 13 months to 16.5 to 17 [months] but it is not that great. A few months. But it was the first targeted therapy ever to get approved in a gynecologic malignancy. And it changed the world in 2014. And then we had to wait. We had to wait for 7 years to get pembrolizumab approved in the same first-line setting. Pembrolizumab is a humanized monoclonal antibody against programmed death-1 (PD-1).

Why would that work in cervical cancer? Well, as I said, cervical cancer is an HPV-related virally induced cancer and that is where checkpoint inhibitors work the best. And so now suddenly, we can take this 16-and-a-half-month survival and boost it to more than 28 months. We can show that when pembrolizumab is added to chemotherapy with/without bevacizumab, you can help women live 1 year longer. I'm not talking about changing the CAT scan progression free survival (PFS). I'm not talking about a few months like bevacizumab, I'm talking about an entire year. And these women on average are around 49 years of age, very young. And then in April 2023, we published in Lancet Oncology that the quality of life (QoL) was not worse if you got more aggressive treatment.

In the olden days patients would say, “I don't want chemotherapy because it's going to make me sick.” No, it's going to make you well, you're going to feel better if you get more aggressive treatment, and you're going to live longer. So that's what KEYNOTE-826 did. This is the result. It got FDA-approved on October 13, 2021, but as a very preliminary result, we didn't really know the magnitude of the benefit. We really didn't know the long-term consequences; we really didn't know the patient reported outcomes (PROs). Now all those boxes have been checked. And now, because of this study, the preferred National Comprehensive Cancer Network (NCCN)-recommended regimen is chemotherapy with/without bevacizumab and pembrolizumab.

PT Staff: Could you discuss KEYNOTE-826?How did pembrolizumab + chemotherapy affect overall survival (OS) and Quality of life (QoL) compared to placebo + chemotherapy?

Bradley J. Monk, MD: Immune therapy has been transformational in oncology, obviously, and some tumors are much more susceptible to immunotherapy intervention. These are tumors that have many neoantigens like melanoma or lung cancer, or tumors that are virally induced, such as nasal pharyngeal, cervical, and hepatocellular in certain circumstances. So the biology here is important. And KEYNOTE-826 was done because of the patients and their families. It was done because of the investigators. And it was done because the sponsor believed in us. And so there's a scientific rationale, and a lot of hard work for a lot of people to change cancer that's unfortunately still among us, particularly here in Arizona among the Latino population, [and] it is an example where there are now very important treatment options.

PT Staff: What could an effective treatment regimen with pembrolizumab look like going forward? (Dosage? Length of treatment? Concurrent medication use?)

Bradley J. Monk, MD: So the chemotherapy, generally carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb) is for 6 doses in KEYNOTE-826, a randomized phase 3 trial of 617 patients. And bevacizumab is added to that unless there was a contraindication and then ultimately, pembrolizumab is added to that in a quadruplet regimen. After the 6 cycles of chemotherapy are done, the pembrolizumab and bevacizumab are continued for 2 years. Every 3 weeks is a maintenance treatment. Now, if bevacizumab is not utilized because of a contraindication, the pembrolizumab can be stretched out to 6 weeks which is obviously more convenient. So, the frequency, or the schedule if you will, of pembrolizumab depends on whether it's a companion with bevacizumab because bevacizumab is a 3-month treatment. Excuse me because bevacizumab is a 3-week treatment.

PT Staff: What does accessibility to this treatment currently look like?

Bradley J. Monk, MD: Cervical cancer, unfortunately, is way too common; not only in the United States but around the world, particularly in marginalized populations or underrepresented minorities. Fortunately, the sponsor has been very generous in providing opportunities wherever these patients who are under resourced can receive this medication, particularly in the United States and around the world. I think the partnership that exists between pharma in pembrolizumab specifically has been very important. And that's relevant to my practice, more than half of the women in Arizona that gets cervical cancer are underfunded, and need assistance programs that the sponsor here is, quite frankly, very pleased to provide and I'm grateful to them.

PT Staff: What further research is needed? Other possible clinical implications/applications?

Bradley J. Monk, MD: So in 2018, based on only 77 patients, pembrolizumab received accelerated approval based on a low response rate of only 14.3%. But when it did shrink tumors, the duration of response (DOR) was long. And then we did KEYNOTE-826 [looking at pembrolizumab] the first-line presented at ASCO 2023, more than a year improvement in overall survival (OS). What's next?

Well, it's obvious. Let's now move it with chemotherapy and radiation. Let's use it the very first time we see a patient with a serious cancer, add it to chemotherapy and radiation so that we can maybe just cure more patients out of the gate so they don't get recurrent or persistent cancer. And that study is finished enrollment—that study is called KEYNOTE A18. A18 hopefully will report soon and hopefully transform the patient experience even more now going from second line to first-line with chemotherapy and radiation. And then moving forward there will be combinations, there will be combinations of PD1 and other agents such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), maybe even a bispecific antibody. And so we're doing what we do clinical trials, and we're doing what we do identify promising agents, bring them earlier in the treatment paradigm, and then exploring novel combinations.

PT Staff: Final thoughts?

Bradley J. Monk, MD: In addition to antiangiogenic bevacizumab, in addition to immunotherapy pembrolizumab, we now live in an era in gynecologic oncology where antibody drug conjugates (ADCs) are becoming increasingly studied. The first ADC approved was in cervical cancer, called tisotumab vedotin (Tivdak; Seagen, Genmab), an ADC against tissue factor which is expressed on virtually all cervical cancers, an ADC that was substantially better than available therapies, which was single-agent chemotherapy, in the second line with a response rate of about 6%. And that's great.

And now, at ASCO, you will see a randomized phase 3 trial with an ADC in ovarian cancer. And we got accelerated approval in ovarian cancer of another ADC against folate receptor Alpha (FOLR) called mirvetuximab soravtansine, and thatstudy in ovarian cancers called MIRASOL. So we're bringing ADCs to the landscape and cervical cancer. Check. And now we're bringing it to the landscape in ovarian cancer. Double check. So we need your help again to identify novel agents such as ADCs and do clinical trials so we can bring them to the clinic so patients can live better and live longer.