Physicians Turn to Molecular Profiling to Drive Treatment Decisions in Endometrial Cancer

Ritu Salani, MD, MBA

More adjuvant treatment decisions are being driven by molecular profiling for patients with endometrial cancer with POLE mutations, mismatch repair (MMR) status, and other genetic alterations dictating the best course of therapy, according to Ritu Salani, MD, MBA. She added that testing can lead to better outcomes while reducing toxicities by optimizing treatment selection.

“We're now moving to a molecular landscape, and profiling is helping to inform treatment strategies. [We are] exploring this further and hopefully personalizing medicine for the first time in this disease,” Salani said in an interview with OncLive^® following a State of the Science Summit^™ on women’s health.

Salani discussed the continued evolution of molecular profiling in endometrial cancer, advances in immunotherapy for endometrial and cervical cancer, and ongoing research in gynecologic cancers. Salani is the director of the Division of Gynecologic Oncology and a professor of Obstetrics and Gynecology at the University of California, Los Angeles (UCLA), Jonsson Comprehensive Cancer Center.

OncLive^®: How has the use of immunotherapy evolved in endometrial cancer?

Salani: It was exciting talking about endometrial cancer, where immunotherapy has changed the landscape regarding treatment. Studies have gone from looking at the recurrent setting and [immunotherapy] in combination with lenvatinib [Lenvima], to now pushing [these regimens] into the frontline. Although we're waiting for these trials to be finalized and reviewed with a data analysis, it's a very promising thing that we're seeing. There is high activity with immunotherapy in this patient population.

[Endometrial cancer] is a little more sophisticated than just [determining if a patient is] estrogen receptor–positive and treating with [hormonal therapy]. We need to look at those molecular mutations and see which patients may be best served by different therapies, reducing toxicities of therapies that may not be the best for [certain] patients.

Even more excitingly, a small subset of patients may be able to have therapy eliminated or deescalated, which may help keep oncologic outcomes favorable without inducing those toxicities.

How has immunotherapy altered the treatment landscape in cervical cancer?

Regarding cervical cancer, immunotherapy continues to be the theme. Checkpoint inhibitors have changed the therapy; we first started with this in the recurrent setting, and now [immunotherapy] has already moved into the frontline setting for those patients with recurrent or advanced cervical cancer.

We are also seeing novel agents come into play. We are starting to see some bispecific targets that look at immunotherapy or checkpoint inhibitors, along with maybe another target in the immunotherapy landscape.

Tisotumab vedotin-tftv [Tivdak], which is an antibody-drug conjugate [ADC] targeting tissue factor, a different mechanism of action that's able to target patients with cervical cancer. We're seeing response rates unlike what we've seen before [with tisotumab vedotin].

Unsurprisingly, combinations of tisotumab vedotin and immunotherapy with checkpoint inhibitors, such pembrolizumab [Keytruda], are also showing some provocative response rates in small groups so far. It is a well-tolerated and exciting regimen that we can look forward to.

In endometrial cancer, how have histologic subtyping and molecular profiling dictated treatment for these patients?

[Sending these tumors for genetic testing] may become the standard practice in those patients where adjuvant therapy is potentially required. The early stage, low-risk patients may not need this, but we will strategize [tumor profiling] by looking for those who have a POLE mutation. Those are the hypermutated tumors that generally have a favorable prognosis, even without adjuvant therapy in advanced stages. It is possible that eliminating or deescalating therapy [could work for] those patients.

If patients don't have a POLE mutation, we look at MMR status. These might be patients who have a more favorable response to checkpoint inhibitors, even in the frontline. We know that in the second line, this is an appealing strategy for these patients with single-agent checkpoint inhibitor therapy with either dostarlimab-gxly [Jemperli] or pembrolizumab. However, moving this to the frontline may be an exciting thing, whether it's in combination with chemotherapy or as a single agent, [although] that has yet to be detailed.

The other molecular profiles that we're looking at are nonspecific molecular profile patterns and P53 mutations. Patients with P53 mutations [tend to] have worse outcomes or a poorer prognosis. These are patients who generally [undergo] chemotherapy, and then we look at other potential targeted strategies that may help improve outcomes. However, we must always be mindful of toxicities.

Those who have a nonspecific mutation profile, we are looking at what strategies may be best for those patients, as they don't have a particular target. How can we optimize their treatment outcomes?

Are you routinely testing for HER2 in endometrial cancer?

We have data [with HER2] in uterine serous carcinomas. For patients with advanced uterine serious carcinomas, I'm routinely testing [for HER2]. We have the luxury of being able to do that at our institution, so that is automatically part of our pathology report.

If HER2 expression is positive, then we treat by adding trastuzumab [Herceptin] to chemotherapy with carboplatin and paclitaxel in these patients.

I'm not doing this universally for all patients with endometrial cancer. We don't have this in other histologic types [with HER2 expression], but it's a provocative idea. Maybe even in ovarian cancer, where we see HER2 expression, there are new ADCs, and these might help make a bigger impact. These therapies are well tolerated, and we're starting to see activity in those who have HER2-low expression. This may open more avenues of treatment for patients who we weren't typically thinking of this strategy for.

The FDA approved frontline pembrolizumab plus chemotherapy for patients with cervical cancer with a PD-L1 combined positive score of at least 1. Although it was a subset analysis, the combination did seem to show benefit irrespective of PD-L1 expression. What are your thoughts about the drug’s current indication and the use of PD-L1 as a biomarker?

We always know that biomarkers leave a little to be desired, but the number of patients who are PD-L1 negative was low, so it's hard to make a conclusion on these patients. We need better strategies for patients across the board, and although this made a difference and [the combination] is FDA approved with PD-L1 expression greater than or equal to 1, it's not curative for most patients.

Interestingly, in the recurrent setting, when you look at some of these patients, cemiplimab [Libtayo] was studied in patients regardless of PD-L1 expression, and we saw a response rate that was comparable, if not a bit better, than patients who were receiving chemotherapy. However, the quality of life was far better. This is something that we must think about. We're not just treating our patients for survival outcome, but also quality of life. If we can provide patients with a little bit of both [survival and quality of life], that is a win.

Excluding the [PD-L1–negative] patients is understandable because it was such a small number. However, I don't know that it completely closes the door on that as an option. It may be beneficial to find [other] combinations, such as with tisotumab vedotin, to create a synergistic effect, which may continue to keep that strategy open for patients who may not qualify for [pembrolizumab plus chemotherapy] in the up-front setting.

Many agents in the pipeline for second-line or later therapy include PD-1 inhibitors. What do we know about subsequent treatment with a PD-1 inhibitor, and is that where tisotumab vedotin is sequenced currently?

After treatment with a checkpoint inhibitor such as pembrolizumab in the frontline, we don't know what the rechallenge experience is going to be like. There are very small numbers of data. I believe that there is a role where tisotumab vedotin is filling a gap for us in the treatment strategy.

There are studies evaluating tumor-infiltrating lymphocytes (TILs) therapy as a post immuno-oncology option, as well as TIL therapy with checkpoint inhibitors. There are some patients who have received prior checkpoint inhibitors. This identifies a huge area of need after patients have received a checkpoint inhibitor and have progression. Are there other strategies that we can use to exploit the immune system? How do we combine that, how do we sequence it, and what do we combine it with? These are all important questions that we don't quite have the answers on yet.

Is there any planned or ongoing research at UCLA that you’d like to highlight?

At UCLA, we have a lot of exciting targets. There is [the phase 3 KEYNOTE-A18 trial (NCT04221945)], a chemoradiation study with the addition of pembrolizumab in locally advanced cervical cancer. That's a study that can cure more patients in the first-line setting.

We have a provocative [phase 2 trial (NCT04712851)] looking at pembrolizumab in patients with cervical dysplasia. This is a new concept and is more a proof of principle. The trial is still ongoing. [We are investigating if] we can we avoid doing surgical procedures on young women who have cervical dysplasia, which may impact future fertility. This is just an exploratory concept, but it's a provocative idea. This shows you that we're thinking outside the box to provide our patients the best therapy and options, not just in the short term, but also in the long term.

Moreover, in endometrial cancer, there's a slew of new studies that are coming out. We talked about the molecular landscape, and some trials are looking to target or exploit those molecular targets in patients with endometrial cancer. We continue to explore how to best sequence [treatments], and we are investigating how to optimize the treatments for the patients based on tumor profiles. These are all exciting topics, and we're constantly learning, so this will never be an ending conversation.