Clinical Trials Explore Novel Targets for Cervical Cancer to Enhance Treatment Efforts

In the management of patients with cervical cancer, the standard of care is still resection of the tumor1, however, select patients may benefit from targeted immunotherapy, bringing into question the role of biomarker testing in this field.

Ritu Salani, MD, discussed the topic in a presentation during the 12th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™.2 Salani, the director of the Division of Gynecologic Oncology and professor in the Department of Obstetrics and Gynecology at David Geffen School of Medicine at University of California Los Angeles, mentioned that novel targets are being explored to advance the treatment landscape for cervical cancers. These targets include HER2 positivity, which may derive benefit from neratinib (Nerlynx) as well as human papillomavirus (HPV) biomarkers like Bintrafusp alfa, HPV 16, and human leukocyte antigen. The study of these targets is ongoing in the clinical trial setting and may shift the field later on, according to Salani.

Further, testing for prognostic factors like mismatch repair deficiency, microsatellite instability, and PD-L1 may help identify better treatment approached for patients.

“I think we are really excited about some of the immunotherapy treatments that are out there in some of the clinical trials, but I question some of their utility for biomarkers. We need to identify how we can select the patients who are most likely to benefit from immunotherapy, she said during the presentation. “I think it’s a shame to exclude patients who are PD-L1-negative when we’re seeing this newer data that show responses in patients who are PD-L1 negative. I think further information needs to be elucidated from these trials.”

In an interview with Targeted Oncology following the medical conference presentation, Salani expanded on the role biomarkers play in the treatment of cervical cancer, how this testing looks in the everyday clinics, and how it can potentially change pending competition of ongoing clinical trials.

TARGETED ONCOLOGY: What is the current role of biomarker testing in cervical cancer?

Salani: Currently, biomarker testing in cervical cancer is not exactly 100%. The most common test that's used is PD-L1 expression or what's called a combined positive score (CPS). That can suggest that patients who have PD-L1 expression may have a better response to immunotherapy. However, trials are still coming out that are showing that maybe PD-L1 expression isn't that important, and patients may still have a response, regardless of expression.

At what point in a patient’s disease is it most important to order testing?

This area is also evolving, and this is one of the really exciting things about cervical cancers, the landscape is changing. Right now, it's FDA approved for a second-line systemic therapy. But I think when a patient recurs, it's important to understand what the options are. Usually, at the time of advanced disease, or recurrent disease, it would be worth testing. And this can often be done in house with the pathology department. A lot of us are doing that at the time of the initial diagnosis just to have that data on hand. So even though the patient may not be a candidate for or need that therapy, you could still have that information on hand, because it's easy to do at the time of the pathology review.

Are there any other targets or prognostic factors you test for? Are any novel targets coming up in the research?

Regarding prognostic factors, one thing that’s becoming more evident in cancers across the board is that the higher the PD-1 expression, the better the response. This still needs to be validated in further studies. But, I think it’s something we’re seeing in our own clinical experience.

How would you compare how far the field of cervical cancer has come in comparison to other gynecologic malignancies?

One of the challenges of cervical cancer is that it’s much smaller in numbers compared with endometrial cancer and ovarian cancer, so the data in studies lag behind. I do think it’s catching up. Ever since the Cancer Genome Atlas was published in 2017, we're learning a lot more about cervical cancer, and not just PD-L1 biomarkers, but other biomarkers such as HER2, that may actually have therapeutic implications. It’s a pretty exciting time in the field.

I think we also need to understand whether these are the best biomarkers and this is something we see in ovarian cancer also. We question how to predict which patients will respond to PARP inhibitors, and in cervical cancer, the question is how to predict which patients will best respond to immunotherapy. This is something that's developing, and I think other opportunities are developing novel agents. Cervical cancers are often considered incurable disease, so understanding what else drives these tumors, and there are a lot of other potential targets including PARP inhibitors. mTOR pathway and many other targets that we haven't even begun to look at.

What clinical trials are underway to help with treating cervical cancers?

There's a lot of activity in cervical cancer and some are biomarker driven and some are not. But I think 1 of the really exciting trials that are happening in cervical cancer are really in the front-line setting. The trial included radiation therapy with immunotherapy. I think this is really exciting because it may be an opportunity to cure patients with advanced disease, and that will potentially be a game changer. There are other studies that are ongoing, both in the United States and globally I think this will be something that we should look forward to seeing.

There are also combinations of different immunotherapy agents in clinical research right now. So, instead of using a single agent, they’re using a dual therapy, and this might actually enhance immune responses in these patients. I think this will help us better understand how to use immune checkpoint inhibitors in cervical cancer.

What advice do you have for oncologists treating cervical cancers in the community setting?

The bottom line is that although the landscape is changing, and it's changing quickly, we still need to do a better job and make sure we're understanding which patients get the most benefit from immunotherapy. We also have to make sure we're not excluding patients who we thought in the past wouldn't get benefit from immunotherapy because they may very well benefit with either combinations of immunotherapy with other agents or other immunotherapy agents. We have to make sure that we're really advancing the field as best we can.

_References:

_{1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Cervical Cancer. March 29, 2019. Accessed May 25, 2021. https://bit.ly/3flhpBi}

_{2. Salani R. Biomarker testing on precision medicine for cervical cancer. Presented at: 12th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies. May 1, 2021; Virtual.}