Salani Sheds Light on the Rising Role of Biomarkers in Cervical Cancer

Partner | Cancer Centers | <b>The Ohio State University</b>

Ritu Salani, MD, discusses the evolving role of biomarker development and testing in cervical cancer.

Ritu Salani, MD

Historically, drug development in cervical cancer has lagged behind other gynecologic malignancies, said Ritu Salani, MD. However, a growing role for biomarker development could be key to pushing the field toward precision medicine and identifying novel therapies for patients with recurrent disease.

"The role of biomarkers is in an early stage," said Salani. "We should continue to enroll eligible patients on clinical trials. This will help us treat patients better."

In June 2018, the FDA granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of patients with recurrent or metastatic cervical cancer who progressed on or after chemotherapy and whose tumors have a PD-L1 combined positive score (CPS) of 1 or more as determined by an FDA-approved test.

"PD-L1 expression can be very informative, but it shouldn't be an all-or-nothing [biomarker]," explained Salani. "Perhaps there are combination therapies that can enhance response rates for patients who have PD-L1—negative disease."

Other biomarkers, such as mismatch repair deficiency (dMMR) and microsatellite instability (MSI), could also indicate eligibility for pembrolizumab monotherapy.

Genetic alternations, such as HER2 mutations and homologous recombination deficiency (HRD), represent a growing area of interest in cervical cancer, explained Salani.

In an interview with OncLive, Salani, an associate professor in the Department of Obstetrics and Gynecology and the director of the Gynecologic Oncology Fellowship Program at The Ohio State University Wexner Medical Center, The Ohio State University Comprehensive Cancer Center—James, discussed the evolving role of biomarker development and testing in cervical cancer.

OncLive: Could you shed light on biomarkers in cervical cancer?

Salani: Cervical cancer is a ripe area of interest right now. The field has lagged behind some of the other gynecologic cancers.

There are some targets in cervical cancer. Immunotherapy has been a growing area of interest in cervical cancer, particularly in terms of PD-L1 expression. Pembrolizumab is FDA approved for use in cervical cancer.

We are also seeing other biomarkers that can [help enrich for benefit with] targeted therapies as well, such as HER2 mutations, which occur in a small subset of cervical cancers.

Other areas of research include combining immunotherapy with other immunotherapeutic agents, such as tissue factor—which is not necessarily a biomarker but is an active agent—and possibly [agents that target] HRD.

What biomarkers should be tested for?

You can use any platform that does tumor molecular testing and you will generally get PD-L1 expression, or what is referred to as CPS. For cervical cancer, [we use CPS to determine a patient’s eligibility] for immunotherapy. You may also get dMMR or MSI status, which can be targets for immunotherapy. The other potential targets are not yet FDA approved.

You may get information that can help inform whether a patient is a good candidate for an active clinical trial, or whether they should be considered for an off-label regimen. Right now, the only [robust] data we have regarding biomarkers is for immunotherapy with PD-L1 expression with a CPS of at least 1%.

Could you highlight some emerging biomarkers?

One that is exciting, although it occurs in a small population, is the HER2 mutation. There are interesting data from a basket trial looking at neratinib (Nerlynx). While it is a small subset of patients, [the data show] that it is a mutation we can act on.

There is also a lot of excitement regarding combination therapies. We know immunotherapy is approved, but the response rates are still relatively low. There is desperate need for therapies that work in cervical cancer. I am hopeful that combination therapy in biomarker-positive patients, and perhaps some who are biomarker negative, may elicit better responses [than historical controls].

How do you approach biomarker testing in practice?

Right now, all these tests are generally reserved for use in the recurrent setting. When you have a patient with recurrent cervical cancer, the standard first-line therapy is general chemotherapy with bevacizumab (Avastin).

We’re hoping that as we get more information to better understand molecular targets and mutations, we’ll be able to move [some therapies] to the frontline setting.

In my practice, I tend to test PD-L1 expression early on so I know whether a patient is an eligible candidate for immunotherapy. This may also help inform whether she is a good candidate for certain clinical trials. I also look for other targetable mutations. [This testing] can still inform treatment.

If patients have advanced or recurrent cervical cancer, they undergo PD-L1 testing for a CPS score assessment to see whether they are a candidate [for immunotherapy]. If they are, that is generally the next line of treatment they will receive.

If the patient is not a candidate [for immunotherapy] or they have progressed [on immunotherapy], implementing a commercial assay can be informative. However, there are other [types] of therapy, as well as clinical trials, that the patient may be a candidate for. That would be highly preferred.

What is the current state of biomarker testing?

One of the nice things about testing is that PD-L1 expression can generally be done in house by the pathologist with immunohistochemistry. Some pathologists are doing it universally while other times, it is requested as a general [assay].

Beyond that, there could be enhanced testing with a commercial assay. However, that could be limited by insurance or financial restrictions.

I hope that [testing] becomes more common, especially as we identify more therapies. Clinical trials are beginning to integrate biomarkers into the protocols, which may also help bring [testing to the forefront] for patients with advanced or recurrent cervical cancer.

What challenges have you faced with biomarker testing?

The biggest challenge is the reimbursement. A lot of patients with cervical cancer come from a lower socioeconomic class and may be underinsured or uninsured. This can be a rate-limiting step.

There are a lot of support programs and financial assistance programs that are offered through institutions. There may even be extra resources available.

How has biomarker testing impacted precision medicine in cervical cancer?

Cervical cancer has been several years behind other gynecologic cancers. Biomarker testing is just now coming to the forefront. As we are seeing better therapies, we can [develop] more informed studies. However, [how we approach treatment] is always going to be [dependent on] proof of principle. Once we know something works in cervical cancer, we can [begin to] understand how biomarkers can inform which patients should receive which therapy.

We are also seeing some biomarker-negative treatments, such as bevacizumab or tisotumab vedotin (HuMax-TF-ADC). These patients may still benefit [from that drug] even though there is no biomarker of response for it. We have to be mindful of that as well.

Are there any research efforts in this space that you are particularly excited about?

With regard to research in cervical cancer, I have a couple of personal biases because I have an interest in PARP inhibitors. We've done a phase 1 study with PARP inhibitors in combination with chemotherapy. We saw some very compelling response rates, and patients appeared to tolerate the regimen well.

Further, we are looking at whether HRD can predict responses to better determine which patients are likely to respond to therapy, which is very exciting.

Understanding PD-L1—negative expression and how that biomarker can help predict patients who may not have [a response to immunotherapy is an important area]. Perhaps we can give those patients combination immunotherapy or chemoimmunotherapy and ultimately, identify other ways to optimize their treatment.

Are there any next steps for the phase 1 study you mentioned with PARP inhibition and chemotherapy?

The phase 1 study did not move on to phase 2, because bevacizumab came out at the same time. Unfortunately, it came down to lack of funding.

Where do you see the future of biomarker testing headed?

If we can, we should perform biomarker studies with HRD status. Then, the next step will be to do a maintenance study with bevacizumab in combination with PARP inhibitors, immunotherapy, or alone in advanced cervical cancer. There are some opportunities to see if these therapies are going to be part of future care.

In terms of the future of biomarker testing in cervical cancer, we should be able to determine which patients will benefit from which therapy early on to see whether we can optimize sequencing on a personalized basis. We may be able to achieve cure, or at least improved duration of response [by doing that]. Right now, it is hard to tell patients who have recurrent cervical cancer that their cancer is likely not curable. If we can use biomarker testing to determine which therapy the patient is most likely to respond to, we may be able to change that statement.

As more biomarkers and treatment options are introduced to the armamentarium, do you foresee challenges regarding sequencing?

The biggest thing that we have yet to figure out is how to determine which patients should receive which therapy, but I think the sequence of therapy should also be explored. We know that many of these patients will be cured, but how do we [determine how best to achieve that]? The challenge is that every time we give patients therapy, their tumor biology changes to some degree. Repeat biopsies are not always feasible, but they may be more informative. This is a challenge we are going to be faced with.