Wenham Discusses the Growing Treatment Landscape Across Gynecologic Cancers

Robert Wenham, MD, MS, FACOG, FACS

Advancements with antibody-drug conjugates (ADCs) in HER2-positive breast cancer and PARP inhibitors in ovarian cancer have transformed their respective treatment spaces, and important strides have also been made in cervical and endometrial cancer, according to Robert Wenham, MD, MS, FACOG, FACS.

“Things are improving in gynecologic cancers, and I’m very bullish that in my lifetime, we will continue to see patients live significantly longer. We may find a couple of these cancers that we can get rid of. I am hopeful that my career will be long enough to get to see that, and hopefully the evolution of this will be fast enough,” Wenham said in an interview with OncLive^® following a State of the Science Summit™ on women’s health.

In the interview, Wenham, who chaired the event, spoke on topics from the meeting including the current treatment landscape for patients with cervical and endometrial cancers, ADCs and PARP inhibitors in ovarian cancer, advancements in HER2-positive breast cancer, and surgical options for patients with ovarian cancer. Wenham is a gynecologic oncologist and the chair of the Gynecologic Oncology Program at Moffitt Cancer Center.

OncLive^®: How has the landscape shifted in the frontline treatment of cervical cancer?

Wenham: I was happy to talk about cervical and endometrial cancer, as these are sometimes forgotten in gynecologic cancers. There has been an abundance of new research that has taken us forward in our understanding of [cervical and endometrial cancer] in the past few years. Although cervical cancer is a minority of gynecologic cancers, it affects a patient population that tends to often be young and in the prime of their lives, [sometimes] with young children or no children, and it can be quite devastating.

We had very few options until the past couple of years. Options included frontline chemotherapy, and a various hodgepodge of chemotherapy after that.

The past decade has brought us forward. That started with the advance of adding bevacizumab [(Avastin) to chemotherapy] in the phase 3 GOG 240 trial [NCT00803062]. That is when we started taking patients that historically had about a 30% life expectancy at 1 year and doubled that to about 60% at 1 year. However, there were issues with patients that would develop fistulas or other problems when they received bevacizumab. What we now know is that about two-thirds of patients will typically choose to be on that regimen for frontline therapy.

The next thing that took us forward was the phase 3 KEYNOTE-826 trial [NCT03635567] utilizing immunotherapy for cervical cancer. What was seen when adding pembrolizumab [Keytruda], a checkpoint inhibitor for immunotherapy, to treatment for patients who received platinum- and taxane-based chemotherapy [with or without] bevacizumab is that [the combination] extended median overall survival [OS] from the GOG 240 trial of 1.5 years to 2 years. What’s been striking about cervical cancer with immunotherapy is that there are some patients that when they hit, they hit well and get durable responses. That is what has been seen for immunotherapy, both in cervical and endometrial cancer.

In what ways have biomarkers started to inform treatment efficacy in endometrial cancer?

In endometrial cancer, a portion of patients can be responsive to immune checkpoint inhibitors. We know a lot more about endometrial cancer just by the virtue of these new drugs that are targeting [specific markers]. We are starting to classify these drugs based upon things like DNA mismatch repair deficiency [dMMR], microsatellite instability [MSI], and DNA polymerase epsilon [POLE] mutations. A number of these cancers can have these [biomarkers] in addition to just PD-L1, which is thought about as a potential [target for a checkpoint inhibitor].

When looking at the phase 2 KEYNOTE-158 trial [NCT02628067], the study had both cervical and endometrial cohorts. In the endometrial cohort, about 45% of patients responded [to pembrolizumab monotherapy]. Moreover, if you look at the lenvatinib [Lenvima] and pembrolizumab data for those who are proficient in dMMR genes, we have very striking data that shows that the combination is superior over chemotherapy, with a hazard ratio improvement of nearly 60%. These are quite compelling data and created a new second-line option for patients after chemotherapy.

The phase 3 LEAP-001 trial [NCT03884101] addressed the question of whether we can move the combination of lenvatinib and pembrolizumab to replace chemotherapy in the frontline. It would be exciting to know that we had more than 1 option because there may be patients who are appropriate for [lenvatinib/pembrolizumab] and some that are appropriate for chemotherapy. Therefore, we could increase our rate of first-line responders.

What are some areas that still need to be addressed across the treatment landscapes in cervical and endometrial cancer?

We are still not curing these cancers. What was remarkable about some of the immunotherapy data was that sometimes responders can go on for years, but that still accounts for less than 10% of patients. We’re still talking about first-line, second-line, and maybe third-line therapy for [these cancers], unlike ovarian cancer, where we have different things we can do for several lines of therapy. Going forward, we’re going to identify subgroups, and we’re going to have a better potential of knowing who’s going to respond up front, based upon these different molecular characteristics.

It was an exciting leap forward looking at uterine papillary serous cancer, where about 30% of patients have HER2 overexpression. That is something that can be targeted to improve OS. As we start understanding [the importance of biomarker testing] up front and we start subcategorizing based upon these molecular markers, we’re going to see those times of progression-free survival [PFS] and OS improving for subpopulations, and the overall population will also improve.

Then we will have better ideas of what to use in second-, third-, and fourth-line treatments. Ultimately, the Achilles’ heel is going to be finding effective immunotherapies, whether that’s cellular therapy or [something else] to treat patients permanently.

What main message would you like to convey from your presentation?

It is an exciting time. We have had a dearth of discovery in many of our cancers for a while, and now the space is exploding with a number of opportunities. However, endometrial cancer cases are still on the rise. While we’ve seen improvement in the numbers of ovarian cancer, we now see the same number of deaths from endometrial cancer every year that we have seen from ovarian cancer. I’m glad that we have therapeutics that are coming ahead of the increase that we’re going to continue to see.

Hye Sook Chon, MD, of Moffitt Cancer Center, spoke on the role of ADCs in ovarian cancer. How could these agents affect the treatment paradigm for these cancers?

The underlying thought behind ADCs is compelling. You have a very targeted therapy that goes to a specific cancer cell that overexpresses something that no other cells in the body do. The ADC delivers toxic poisons that we couldn’t normally give a patient [directly to the cancer cells]. One of the Achilles’ heels of this program for several years was what links the antibody with the target to the poison itself. [Technological advances have made] linkers better so they release the poison when you want to. That has been what’s brought ADCs forward, because there have been a lot smart people working on this for a very long time, but it is the linker mechanism that has made this viable.

We see with mirvetuximab soravtansine [IMGN853] for patients that overexpress folate receptor alpha [FRα], that is a good target because it’s overexpressed in the vast number of ovarian cancers. We’re seeing responses [with mirvetuximab soravtansine], even in combination, that are making us excited about potentially either adding to it chemotherapy or replacing chemotherapy altogether.

What key clinical trials exploring ADCs in ovarian cancer are you most excited about?

There are a number of combinations, and we are interested to know what’s going to be the combination with platinum-based chemotherapy. We are interested to know if the combination of that with other agents, such as anti-VEGF and immunotherapy, are going to be viable options. There are other drugs that are being explored that are ADCs, including tisotumab vedotin-tftv (Tivdak) in ovarian cancer, which is being explored both by itself and in various combinations.

Moreover, there are other potential targets for ADCs. We have yet to find out which of these targets are going to be completely successful. My hope is that we’re going to find several of them are successful, and then we find patient populations that can be triaged based upon those markers. We would then have a therapeutic option for each patient who walks into clinic, depending upon what their cancer expresses.

Jeannie Chern, MD, ScM, of Moffitt Cancer Center, spoke on PARP inhibitors in ovarian cancer. Does the presence of BRCA mutations continue to drive PARP inhibitor decisions for this patient population?

Those of us who are close to ovarian cancer almost feel [overwhelmed] because there has been so much data [on PARP inhibitors], and it’s been very good data in favor of patients who have BRCA mutations. We’ve already seen it in the phase 3 SOLO2 trial [NCT01874353] data [on the use of olaparib (Lynparza) vs placebo in patients with ovarian cancer who responded to platinum-based chemotherapy]. SOLO2 showed an OS benefit by over a year in median time [with olaparib]. Those kinds of numbers are staggering. When you look at the separation of these curves, even after patients have discontinued the PARP inhibitor, it tells you that we’ve hit on something more exciting than PARP responders. We know that patients with BRCA mutations are the best responders to PARP inhibitors, and we know patients who are homologous recombination deficient [HRD], non-BRCA mutated are that second group. There are some response elements seen in the homologous recombination proficient group as well, though it is more debatable about how much of a benefit is seen.

The real target of research now is that we’ve understood some basic biology of these cancers because of these therapeutics, and we’re able to start looking at mechanisms, not just a response. It’s more interesting to look at the non-responders. There are various combinations out there, such as ATR inhibitors or WEE1 inhibitors, that are being explored to overcome PARP resistance and make more patients respond. That story is still developing in the non-responders.

Overall, PARP inhibitors have completely changed the way we practice in our molecular diagnostics, in our opportunity to exploit better outcomes for some patients, and in our standing and treating cancer in general.

How do you determine if a patient with ovarian cancer needs biomarker testing? What are some of the key biomarkers that are tested for?

If you have patients with ovarian cancer, get biomarker [testing]. Send samples for somatic testing and germline testing [after diagnosis]. Somatic testing picks up a vast majority of germline mutations but not all of them.

Moreover, the categorization is important because we have BRCA mutations, but there are many mutations that lead to BRCA likeness, which is now called HRD. About half of patients with ovarian cancers are HRD, and we can exploit that in different ways. Dr Chon discussed some of the data in the phase 3 PAOLA-1 trial [NCT02477644] combining olaparib with chemotherapy with or without bevacizumab.

It is important to test [for biomarkers]. If an oncologist is not used to doing genetic testing and counseling in this area, collaborate with a geneticist or an oncologist who has experience in this area.

Heather Han, MD, of Moffitt Cancer Center, spoke on therapies for HER2-positive breast cancer. How has the emergence of more targeted therapies affected treatment options for patients who have HER2-positive disease?

It was nice to hear her talk about the evolution of HER2 in breast cancer. I was surprised to hear about the number of different HER2-targeted therapies and some of the dilemmas they’ve had in looking at biomarkers and knowing the best combinations to use.

It was exciting to see the data from the 2022 ASCO Annual Meeting that she presented, showing an improvement in outcomes with some of the ADC-type HER2 targets, and it makes me think about in gynecologic cancers the potential to exploit similar targeting now that we’ve seen HER2 be a big success, at least in endometrial cancer.

Mitchel Hoffman, MD, of Moffitt Cancer Center, spoke on changes in surgery for ovarian cancer. What factors play a role in deciding which patients are ideal candidates for surgery?

We keep finding that there’s more opportunities to explore in this space. One of the big things is if you’re going to debulk in ovarian cancer, you have to select patients appropriately. Unfortunately, what we see too commonly due to neoadjuvant data showing the possibility of giving 3 or 4 cycles of chemotherapy first, was a bit of an overinterpretation of that data. We see that patients are often getting 6 cycles, and we see that the opportunity to improve outcomes drops off in some of the retrospective analyses when giving additional cycles past 3 or 4.

There’s data to suggest that you most likely want to give that opportunity for an optimal surgery as early as possible so those who can get it before chemotherapy, who have less bulky disease, and are well selected, may do better than receiving neoadjuvant chemotherapy. You have to select patients for neoadjuvant chemotherapy appropriately.

Additionally, the development of an ability to detect more cancer is exciting. The pafolacianine [Cytalux] data showed that 27% of patients could have 1 cm or greater lesions detected using a laser camera at the time of surgery. This means that at least 1 in 4 patients will now be rendered even more optimal than we thought they were going to be. We know getting down to microscopic residual disease leads to longer survival. We have new technology, and we are happy to be part of phase 2 and phase 3 of the development of [pafolacianine]. We are offering that to patients.

The other thing out of surgery was who to operate on [a second time. After we’ve done the surgery and they’ve had a recurrence, Dr Hoffman spoke on the 3 big trials that have tried to address this. What we’ve learned is that patient selection is what makes the difference. You have to pick the patients who have had a long treatment-free interval, those who have very few sites of disease, lack of carcinomatosis, good performance status, and had a good response to chemotherapy the first time. [Factors] that many of us had sensed have been codified now in good clinical trial data.

Is there any research at Moffitt Cancer Center that you’d like to highlight?

To summarize everything, we’ve been talking about, all these steps forward have been made because of research, which has kept the benchmark moving forward. I encourage any patient or any physician, who may be wondering whether to refer a patient for a clinical trial, to do so. Referring a patient early with good performance status [is important]. Don’t wait until you feel you’ve exhausted every option, because sometimes this excludes patients from the opportunity to ever be involved in these novel trials, which are leading us forward.

There are opportunities at Moffitt Cancer Center for ADCs. We have some that are targeting FRα that are available at our institution. We’re interested in some of the anti–PARP-resistance mechanisms using WEE1 and ATR inhibitors. We have a CAR T-cell therapy trial, which is a specific trial for our institution that is targeting the follicle stimulating hormone receptor. The list goes on, but these things are great opportunities for patients to come in and be involved in what we think are going to be tomorrow’s treatments today.