Jessica Hergert

The FDA approvals of pembrolizumab (Keytruda) and dostarlimab-gxly (Jemperli) emphasize the need to test for microsatellite instability–high (MSI-H), mismatch repair deficient (dMMR), and tumor mutational burden–high (TMB-H) tumors in endometrial cancer, said Sarah Lee, MD, MBA, who added that testing for these molecular features will ensure immunotherapy is tailored to appropriate patients.

“The alphabet soup [of these disease features] could be very confusing [for patients]; it is certainly confusing for me as well. What is important for patients is that they look beyond just the histology of their cancers and get as much information as they can so that they are able to get therapies they are eligible for based on some of these biomarkers,” Lee explained.

® during the SGO 2022 Winter Meeting, Lee, a first-year fellow in the Department of Obstetrics and Gynecology at NYU Langone Health, discussed the use of checkpoint inhibitors in endometrial cancer, research regarding the association between MSI-H, dMMR, and TMB-H disease, and the importance of broad molecular testing to ensure all eligible patients are appropriately matched to immunotherapeutic options.

®: How has immunotherapy changed the landscape of endometrial cancer management?

: Several FDA indications [have been granted] for patients with endometrial cancer. For pembrolizumab, there was an FDA approval in 2017 for patients with MSI-H or dMMR disease. Then in 2020, [another indication was granted to pembrolizumab] for TMB-H [solid tumors]. Then, the results of the GARNET trial [NCT02715284] came out, which brought forth dostarlimab, another checkpoint inhibitor, which was approved for patients with dMMR disease in April of 2021.

We are excited about all these expanding indications for endometrial cancer, but we really want to know what the overlap of [MSI-H, dMMR, and TMB-H] is and their associations so that we can maximize our patients who qualify for immunotherapy

During the SGO 2022 Winter Meeting, you presented findings from a study looking at the association between MSI-H, dMMR, and TMB-H disease features in endometrial cancer. What was the rationale to evaluate this topic in the context of these FDA approvals?

The main goal of our study was to determine the association between TMB-H and MSI-H/dMMR; 16% of our patient cohort had all 3 [markers]. When we looked closer at the patients who were not MSI-H/dMMR, 5% were found to be TMB-H alone. These patients would have been missed if we just did MSI and MMR testing alone.

We wanted to hit home that patients are likely getting a mixture of testing that is institutional and provider dependent. If we don’t [test for all potentially relevant markers] and get the tumor molecularly profiled, we have the potential to miss a subset of patients, mainly the TMB-H patients, who would otherwise be eligible for immunotherapy.

Did you find any of these results particularly surprising?

The findings that were interesting to us [were] when we looked specifically at the 6 patients who were found to be TMB-H without being MSI-H/dMMR. That is a cohort that would have been missed with just MSI/MMR testing alone. We found that in this subgroup of patients, 5 of the 6 were non-Whites and 5 of the 6 had non-endometrioid, high-risk histologies. This is in comparison to the group who met all 3 criteria of [having] TMB-H, MSI-H, and dMMR disease. In that group, only 12% of patients had non-endometrioid histologies.

Yes, our n is small, but perhaps the signals that the group of patients who are TMB-H alone [had are] different [from those in a] subset of patients with cancer characteristics that are associated with a worse prognosis.

What other aspects of the SGO 2022 Winter Meeting were intriguing to you that you could bring back to your practice? What research needs to be done with molecular subtyping in endometrial cancer?

It’s been inspiring to be here at the SGO 2022 Winter Meeting. In the uterine section, there was a lot of talk about type 1 and type 2 endometrial cancers. Really diving deeper into the molecular subtypes as evidenced by TCGA [(The Cancer Genome Atlas) is exciting].

There is a lot of movement in the field [of endometrial cancer] to decipher what it means to have one of these clinical molecular subtypes at the patient level. Our data are very small and limited to a single-institute case series, so we need to validate it. We plan to do that with a multi-institutional endometrial cancer consortium moving forward to see what the associations are between these 3 entities and take a closer look at these patients who are TMB-high alone to see if we can validate our findings.

What other patient populations could this research affect?

One of the important findings is that if we just limit ourselves to certain types of testing, like MMR testing, we are missing large [populations] of patients. This is important for Lynch syndrome because MMR testing is not 100% [effective] for diagnosing Lynch syndrome. This has important implications for patients, but also for their families in terms of cascade testing. It is important to molecularly sequence our patients so that we can maximize their chances of being eligible for some of these exciting immunotherapies.

This article was initially published by our sister publication OncLive.

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Sarah Lee, MD, MBA, discusses the use of checkpoint inhibitors in endometrial cancer, research regarding the association between MSI-H, dMMR, and TMB-H disease, and the importance of broad molecular testing to ensure all eligible patients are appropriately matched to immunotherapeutic options.

 Immunotherapy approvals shine light on need for molecular testing in endometrial cancer

Improved risk assessment and imaging strategies have underscored the need for early disease detection in patients with breast cancer, said Paul Lawrence Baron, MD, who added that early identification can capitalize on less morbid therapeutic approaches, such as lumpectomies, systemic targeted therapies, and hyperfractionated radiation therapy.

“[We’ve seen] a lot of things to be optimistic about [in the management of] breast cancer. Survival seems to be [improving], and we are using less morbid treatments for these patients,” said Baron, chief of breast surgery and director of the Breast Cancer Program at Lenox Hill Hospital of Northwell Health, in an interview with 

® during an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

The virtual meeting covered the identification and management of patients at high risk of developing breast cancer, strategies for treating patients with early-stage and metastatic HER2-positive breast cancer, updates in breast imaging, and controversies surrounding breast radiation therapy.

In the interview, Barron discussed best practices for determining a patient’s risk of developing breast cancer, the significance of targeting HER2 in patients with early-stage and metastatic disease, and remaining questions with radiation therapy in the field.

®: What are the current means of determining someone’s risk of developing breast cancer?

: We frequently use the Tyrer-Cuzick model, which is a calculated model that gives us an idea of what the patient’s lifetime risk is. If [the risk] is over 20%, those patients are considered high risk and require close imaging follow-up. If [the Tyrer-Cuzick score] is 15% or less, they are average-risk patients, and [those patients] don’t require [close imaging follow-up].

In the high-risk patients, in addition to doing 3D mammograms, we frequently use breast MRI as a supplement [follow-up technique].

What factors contribute to someone’s risk of developing breast cancer?

A high-risk patient is somebody who has inherited a gene that increases their risk of breast cancer. The most common [alterations] we talk about are 

. We also look at whether the patient has a previous history of radiation to their chest because those patients have an increased risk for developing breast cancer. [Other] patients with a high risk of developing breast cancer [include those with] a very strong family history but [without] a known genetic mutation, those who have had a previous biopsy that showed atypical hyperplasia or lobular carcinoma in situ, or those with dense breast tissue. Those are some of the high-risk features that we identify in patients and [in whom] require very close follow-up.

During the IPC meeting, Lisa Baron, MD, of Northwell Health discussed updates with breast imaging. What are some best practices for screening patients who are at risk of developing breast cancer and how could improving imaging techniques benefit patients?

The most common recommendation is to do 3D mammography on patients. That is the best way of screening patients. We recommend getting a baseline mammogram on somebody 40 years of age and then once a year going forward. If the patient is high risk, we frequently supplement [3D mammography] with a breast MRI, which is done about 6 months later. We try to alternate one test with the other every 6 months. Those are the common [tests], but we frequently also use breast ultrasound, which helps with mammogram as a screening tool.

Those are the 3 main modalities commonly used and strongly advocated for in screening patients for breast cancer. However, some new techniques are coming down the pike that we learned about [during the IPC meeting] from the imaging portion. [Some of these techniques] include contrast-enhanced mammography, which is for patients who, for various, reasons don’t want to or can’t have an MRI. [In these cases], patients get a small amount of contrast with the mammogram. It’s a very sensitive way for finding additional lesions that are not well seen on the mammogram.

Francisco Esteva, MD, PhD, of Northwell Health, spoke to management strategies in HER2-positive breast cancer. How has the integration of trastuzumab (Herceptin) and pertuzumab (Perjeta) transformed clinical practice in the neoadjuvant and adjuvant settings?

Clearly, it was a huge success story in identifying that patients who have HER2-positive cancer benefit from trastuzumab and pertuzumab, which lowers their risk of the cancer coming back. In patients who require neoadjuvant therapy, we see their tumors disappear. Patients who get [trastuzumab and pertuzumab] as adjuvant therapy have a very low risk of the cancer coming back. It was a huge success in breast cancer treatment in the past 20 years.

Next, Anna Komorowski, MD, of Northwell Health, discussed treatment approaches in HER2-positive metastatic breast cancer. What does it mean for the field to have HER2 as a target in the metastatic setting?

Although we are never happy to see someone with metastatic disease, we were very happy to have a target with HER2 [emerge] because at least then we had something to target. We have a lot of answers and new drugs coming down the pike targeting patients with metastatic HER2-positive breast cancer to improve long-term outcomes.

Finally, Seth R. Blacksburg, MD, of Northwell Health, commented on controversies surrounding breast radiation therapy. How do you view the role of axillary lymph node radiation in breast cancer

In the past, the standard treatment was that if somebody had a positive lymph node, we would do an axillary lymph node dissection. However, the data have shown that if patients have a positive node, they do just as well from a survival standpoint with axillary radiation therapy vs axillary dissection. [Patients who undergo] axillary radiation therapy seemed to have less morbidity vs those who have axillary [dissection]. There is a lot of promise for using axillary radiation for those patients.

What key points from the IPC meeting should be underscored for the breast cancer community?

The take-home message is for those dealing with breast cancer, we have made huge strides in identifying patients at a high risk of developing disease. Certainly, if we identify those patients with cancer early, they get a better chance at survival and a lower likelihood of needing a mastectomy. When we find [the disease] early, it is small and treatable.

We have a lot of advances in imaging, so we are helping to find these cancers early. Most of my practice is outpatient surgery because most patients can have a lumpectomy and do not require mastectomies these days. We still do mastectomies on a selective basis, but that is in a minority of cases.

We have made huge advances in systemic therapy, especially with targeted therapy against the HER2 protein. [This has led to] major changes in outcomes for patients.

Finally, people use to believe that radiation therapy was a high-morbidity treatment. However, in many ways, [radiation therapy] has become less morbid than some of the other surgical modalities we are doing. In many cases, patients don’t need radiation, or if they do, it is a shorter course of hyperfractionated radiation.

This article was originally published on OncLive®. 

Paul Lawrence Baron, MD, discussed best practices for determining a patient’s risk of developing breast cancer, the significance of targeting HER2 in patients with early-stage and metastatic disease, and remaining questions with radiation therapy in the field.

Breast cancer paradigm moves toward less morbid treatments with improved risk assessment and imaging strategies

Immunotherapy is emerging as a preferred second-line treatment option for patients with gynecologic cancers, including endometrial and cervical cancer, said R. Wendel Naumann, MD, who added that checkpoint inhibitors may also be preferred to chemotherapy in the frontline or adjuvant settings based on improved efficacy.

“In endometrial and cervical cancers, we are seeing that immunotherapy is not only effective, but is probably more effective than chemotherapy,” said Naumann, a gynecologic oncologist at the Levine Cancer Institute of Atrium Health. “[Immunotherapy] is being taken into the frontline setting. We are steadily moving from recurrent, second-line treatment to frontline treatment or even adjuvant immunotherapy.”

However, immunotherapy has been more difficult to integrate into the treatment paradigm of ovarian cancer, although personalized combination-based approaches may hold utility.

“In ovarian cancer, we have to be a little bit smarter in terms of how we treat patients with immunotherapy. Certainly, some patients respond to immunotherapy, but we need to have a better strategy than giving a single treatment to everybody. [We need to] individualize therapy based on the profiling of these ovarian cancers,” Nauman said in an interview with 

® during an Institutional Perspectives in Cancer webinar on gynecologic malignancies.

The virtual meeting covered a range of topics in gynecologic cancers, including updates in endometrial and cervical cancers, as well as novel immunotherapy strategies and second-line maintenance therapy in ovarian cancer.

In the interview, Naumann, who co-chaired the event, discussed the current state of immunotherapy in gynecologic cancers, as well as key updates across the field.

®: What shifts are being seen regarding the treatment of patients with endometrial cancer?

: Endometrial cancer is a great topic because there are a lot of exciting data coming out. The landscape is going to change quite a bit. The big news is that immunotherapy is probably how we are going [to treat patients in] the second-line setting. We now have progression-free survival [PFS] and overall survival [OS] data suggesting that immunotherapy in the second-line setting is better than chemotherapy. This is even in the mismatch repair-proficient [pMMR] cancers that are typically not thought to be as immunogenic as the mismatch repair deficient [dMMR] cancers. That is with the addition of lenvatinib [(Lenvima) to pembrolizumab (Keytruda)], which probably alters the microenvironment and increases the immunogenicity of the cancers so that they can basically be attacked by the immune system. We have seen great efficacy of the combination, both in endometrial and serous cancers, which is an area of high unmet need.

As this [research] develops, we are going to see more immunotherapy moving to the frontline setting. It may be that we will combine immunotherapy with frontline chemotherapy. We may use immunotherapy instead of frontline chemotherapy. We may combine immunotherapy with radiation therapy going forward in the intermediate- or high-risk groups that have significant risk for local or distant failure and are getting treated with adjuvant radiation therapy.

This is an exciting and pivotal time for the evolution of immunotherapy in endometrial cancer.

How could combining immunotherapy with VEGF inhibitors overcome some of the challenges seen with single-agent immunotherapy in endometrial cancer?

The problem with immunotherapy is that a patient can develop immune tolerance. Although a tumor may elicit an immune response, we have downregulation of that immune response in the form of immune tolerance. This is probably mediated in the tumor microenvironment to a large degree by VEGF. It makes sense that VEGF inhibition would potentially alter that immune tolerance.

We don’t quite understand how that works, but it certainly is interesting that, at least in the example of lenvatinib plus pembrolizumab, it appears that the combination of those 2 agents is better than either agent alone, suggesting that there is a synergy. [Such pathway inhibition] is truly something that is necessary in terms of eliciting responses.

What studies have contributed to the field’s understanding of immunotherapy in endometrial cancer?

KEYNOTE-164 [NCT02501096] set the stage for second-line immunotherapy with the phase 2 data that were presented. KEYNOTE-775 [NCT03517449] was the confirmatory trial that suggested immunotherapy was better than chemotherapy both in terms of PFS and OS. This changed the standard of care in patients with advanced endometrial cancer, even pMMR cancers.

The ROSCAN trial [NCT03651206] is probably going to give us some sense as to whether the combination of immunotherapy and PARP inhibition is potentially efficacious in endometrial cancer. We certainly hope it is. That is a 3-arm trial, so if the combination of dostarlimab with niraparib [(Zejula) is more efficacious vs niraparib or chemotherapy] and is taken to the phase 3 portion of the trial, that will be a very important step in terms of looking for other agents that are potentially added to immunotherapy.

Robert L. Coleman, MD, FACOG, FACS, of The US Oncology Network, talked about updates in locally advanced cervical cancer at the IPC meeting. Could you speak to the data we have seen with *tisotumab vedotin-tftv ((Tivdak) and why it could be an important agent in cervical cancer? What about other immunotherapies?

Just like in endometrial cancer, the landscape of cervical cancer is [expanding] very quickly. With the recent data, it is very likely that immunotherapy with checkpoint inhibitors plus chemotherapy is going to be the standard of care for frontline recurrent or metastatic cervical cancer. We know these agents like pembrolizumab are good and approved as second-line agents.

Several trials are ongoing of combination checkpoint inhibitors, including anti–PD-1 and anti–CTLA-4 antibodies. These trials are exciting, but if we move immunotherapy to the frontline setting, what are we going to use for second-line therapy? Tisotumab vedotin will probably fill that gap.

Tisotumab vedotin is an important drug [in cervical cancer]. Tisotumab vedotin is an antibody-drug conjugate [against] tissue factor. There will be some challenges with some of the toxicities and mitigation of those toxicities, particularly ocular toxicities. However, the responses are very good with that agent. We were in a situation where frontline therapy had a very marginal response rate until GOG-240 [NCT00803062] with the addition of bevacizumab [(Avastin) to chemotherapy]. Now we are talking about second- and potentially third-line chemotherapy or therapeutic agents. That is a great advance, especially in cervical cancer where many of our patients are very young.

We will see how this shakes out, but I suspect that immunotherapy will be [used in the] frontline [setting]. Then we will have to decide exactly what order to put our second- and third-line agents in.

Thomas Herzog, MD, of NewYork-Presbyterian Hospital, discussed the phase 3 PRIMA study (NCT02655016), which evaluated niraparib vs placebo as frontline maintenance treatment in ovarian cancer. Could you highlight the key efficacy and safety findings from that study?

The PRIMA trial showed that the addition of niraparib as a main strategy in frontline ovarian cancer was basically beneficial across the board, regardless of homologous recombination deficiency [HRD] status. That simplifies decisions to discuss maintenance therapy with a PARP inhibitor, which is pretty well tolerated for the most part, with patients with ovarian cancer.

As we would expect, the PRIMA trial showed that patients with HRD are going to benefit more [from niraparib] compared with patients with homologous recombination proficient tumors. There are some subtleties in terms of counseling and whether these patients are going to benefit based on the toxicity of the drug. I use [those factors] to help patients make a shared decision of whether they want to go on maintenance therapy, or even potentially look for experimental options if they have poor-prognosis tumors.

Angeles Alvarez Secord, MD, of Duke Health, spoke about second-line maintenance therapy in ovarian cancer and the utility of PARP inhibitors in platinum-sensitive disease. What updates have been seen here?

The updates have confirmed that patients with platinum-sensitive ovarian cancer respond well and benefit from PARP inhibition. We don’t need to use HRD testing in that setting. Those data are not surprising.

There has been some resistance to the use of maintenance therapy in platinum-sensitive ovarian cancer. That’s tradition more than based in science. Maintenance therapy, both in the frontline and the platinum-sensitive recurrent settings, is the standard of care, or at least the discussion of maintenance therapy with patients in those settings is.

Lastly, Ritu Salani, MD, of UCLA Health, discussed immunotherapy and novel strategies in ovarian cancer. What is the current role of checkpoint inhibitors here, and what novel strategies are you keeping an eye on?

Ovarian cancer has been difficult. We had a large flurry of up-front trials utilizing checkpoint inhibitors, PARP inhibitors, and VEGF inhibitors with a lot of promise. Unfortunately, those trials to date have not been positive. We have a few more trials to read out, but the enthusiasm for the up-front use of multiple agents in the maintenance setting is dampened by the data we’ve seen so far.

I am interested in the LEAP-001 trial [NCT03884101], which combines a checkpoint inhibitor with lenvatinib. That is potentially going to be beneficial. We certainly saw benefit in endometrial cancer, which has a similar response profile to ovarian cancer, particularly serous ovarian cancer. That is an exciting combination, but we will have to see if that plays out in that patient population.

We are going to get better [at tailoring therapy] with time. It is just a question of which strategy will work in which patients and how granular we have to divide patients out to find treatments that work.

This interview took place prior to the September 20, 2021, FDA approval of

tisotumab vedotin for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This article was initially published by our sister publication Onc Live.

Immunotherapy is emerging as a preferred second-line treatment option for patients with gynecologic cancers, including endometrial and cervical cancer. Checkpoint inhibitors may also be preferred to chemotherapy in the frontline or adjuvant settings based on improved efficacy.

Jessica Hergert

Articles

Immunotherapy approvals shine light on need for molecular testing in endometrial cancer

Breast cancer paradigm moves toward less morbid treatments with improved risk assessment and imaging strategies

Single-agent and combo immunotherapy as second-line treatment of gynecologic cancers