Immunotherapy Shakes Up Cervical Cancer Treatment Paradigm

The FDA approvals of pembrolizumab (Keytruda) and tisotumab vedotin- tftv (Tivdak) have brought much-needed options to patients with metastatic or recur- rent cervical cancer, respectively, explained Lt Col Yovanni Casablanca, MD, who added that PD-L1 is now a must-test biomarker.

“When you have recurrent or metastatic cervical cancer that’s not amenable to surgery or localized treatment with radiation, PD-L1 testing with the assessment of the combined positive score is important to get as soon as you can so that you can decide on the appropriate first-line treatment regimen. Chemotherapy is not going away, and the use of bevacizumab [Avastin] is not going away, but [PD-L1 testing] will help you decide whether you want to add pembrolizumab to that backbone,” Casablanca said.

In an interview with Targeted Therapies in Oncology (TTO), Casablanca, a lieutenant colonel in the Air Force, program director of the National Capital Consortium’s Fellowship in Gynecologic Oncology at the Walter Reed National Military Medical Center, and asso- ciate professor, Department of Gynecologic Surgery and Obstetrics, School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, Maryland, discussed the incorporation of new treatments into the cervical cancer paradigm and provided insight into the necessity of inclusive research with novel therapies.

TTO: You discussed the incorporation of new cervical cancer drugs into your practice at the Society of Gynecologic Oncology (SGO) 2022 Winter Meeting. What pivotal approvals have affected your practice for women with cervical cancer?

CASABLANCA: Since the last SGO Winter Meeting that we had 2 years ago, there have been some breakthrough approvals from the FDA for use of new sys- temic treatment regimens in metastatic or recurrent cancer. One of those approvals is the addition of pembrolizumab to chemother- apy and bevacizumab in the first-line setting for cervical cancer based on data from the KEYNOTE-826 trial [NCT03635567].

After first-line treatment, there are a lot of promising options in the second-line setting. We have other immunotherapies that hopefully will be approved soon, possibly without the need for PD-L1 positivity, although we’ll see what the FDA decides. The other breakthrough was the approval of a new novel drug called tiso- tumab vedotin, which is an antibody-drug conjugate that is now approved in the second-line setting. The agent had remarkable duration of response, immediacy of the response, and overall survival [in the pivotal trial]. Compared with where we were 2 years ago, that’s a big improvement. Despite the challenges of the pandemic, there have been some breakthroughs and progress in the treatment of patients with metastatic and recurrent cervical cancer.

One of the things that was on community members’ minds, particularly with tisotumab vedotin is that this class of medicine is associated with ocular adverse effects [AEs]. There is a need for partnership with an eye care professional such as an optometrist or an ophthalmologist with knowledge of these AEs when you use this drug in the second-line setting, which is not a very common relationship. We don’t usually have our offices next door to an eye care profes- sional. A lot of [individuals] are not sure how they’re going to navigate and establish those relationships, but I discussed why it’s important to do so: There is an FDA blackbox warning about the ocular AEs. Thankfully, we have a mitigation and management plan for these ocular eye AEs. Proactiveness and educating the patient on the importance of their eye care plan will help to make this hopefully not as big of an issue.

What has been the biggest change in practice with the approval of pembrolizumab in the first-line setting?

For patients with metastatic and recurrent cervical cancer, the standard had been to utilize 2 chemotherapies and consider adding bevacizumab to it. That 3-drug regimen was our standard 2 years ago. Now with the data from KEYNOTE-826, for patients who have PD-L1–positive tumors, we can add pembroli- zumab to that regimen. The biggest change for clinicians is wrapping their head around using 4 drugs at the same time, potentially, to treat patients with metastatic or recurrent cervical cancer and getting PD-L1 biomarker testing as soon as this diagnosis is made, so that they can choose whether they’re going to add pembrolizumab [to that standard 3-drug regimen].

What are some of the disease-specific challenges of developing novel therapies for patients withcervical cancer?

Cervical cancer is a unique disease and patient population for us com- pared with endometrial and ovarian cancer. Metastatic and recurrent cervical cancer is not as common in our practice. [Cervical cancer] is not a very common disease over- all, so that’s one challenge. One of the unique things about patients with cervical cancer is that they’re quite young overall. [Women with cervical cancer] are very young, other- wise healthy women, sometimes with families and children. It’s an important population, even though it’s a smaller popu- lation to focus on. The other thing that is important to highlight is that cervical cancer and advanced cervical cancer...is an even bigger problem worldwide in underdeveloped countries or countries where preventive care is less robust. A lot of the breakthroughs that we have in the United States may not be as applicable globally. It is a very niche type of research that’s done with these advancements, because it’s a smaller population with needs that vary from country to country. The population is very heterogenous too, even in the United States.

What therapeutic class has the most potential to make an impact on the treatment paradigm?

With immunotherapy and immuno- therapy combinations—not just pem- brolizumab-based combinations, but other immunotherapy combinations and novel immunotherapy agents, such as TIL [tumor-infiltrating lymphocyte] treatment— there is a growing amount of knowledge in the role of the immune system and the poten- tial hope we have in immunotherapy, not just as single agents but also in combination with standard regimens. I don’t think that the future of cervical cancer is going to hang on giving 1 drug at a time. I think the future of cervical cancer treatment is going to be using combinations of multiple treatments to see improvement in survival.

What can be done to make sure that these developments reachvthe community at large?

There are significant disparities in our country’s health care system. [Patients with] cervical cancer have a vast demographic makeup with many cultural and racial ethnic backgrounds. By allowing and supporting clinical trial enrollment for every [individual] and population, we hope to improve the extension of these novel therapies to popula- tions or subsets that normally wouldn’t have had access to them. There certainly is a lot of work to do to reach out to patients who are under[insured] or noninsured and patients who don’t have access to larger or tertiary medical centers with novel therapies available.

Is there any research you’re involved in that you’d like to highlight?

So much activity is going on now in cervical cancer trials across the coun- try, including the addition of immunotherapy to the chemoradiation backbone for locally advanced disease and looking at combinations of therapies. Now that patients are getting immunotherapy in the first-line setting, [we are asking,] what do we do with immuno- therapy if they progress and need something in the second-line setting? Should patients get immunotherapy again? Should we switch classes? How do we make immunotherapy effective and tolerable at the same time?

The trial that I’m involved in in the cervical cancer field is looking at adding triapine, which is a novel drug, to the backbone of chemotherapy and radiation in locally advanced cervical cancer.