Novel Strategies Emerging in Uterine Sarcomas

Suzanne George, MD

While chemotherapeutic approaches are available for patients with uterine sarcomas, research is moving in the direction of novel combinations, biomarkers, and collaboration, explained Suzanne George, MD.

Regimens that include gemcitabine plus docetaxel, and agents such as olaratumab (Lartruvo), trabectedin (Yondelis) and pazopanib (Votrient) have been a staple in treatment approaches. Now, some of these agents are being evaluated in combination, while the PI3K and mTOR pathways are becoming of interest.

“As a field, we need to figure out how to be better at proactively identifying patients at higher risk for an underlying malignancy, and how to work collaboratively as a field in order to bring the best care to our patients,” said George, director of Clinical Research, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, and an associate professor of Medicine, Harvard Medical School.

OncLive: What is the current state of uterine sarcoma management?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, George highlighted the available therapies for patients with uterine sarcomas and what novel options are on the horizon.George: [At the State of the Science Summit™] I discussed systemic therapies in uterine leiomyosarcoma, specifically the role of chemotherapy in patients with advanced or metastatic disease. A key point is that there is an increasing number of systemic options available for patients with this disease, with a number of new approvals over the last several years and some promising agents that are currently under development.

I was very appreciative to be invited to participate in this talk [at this meeting]; I know that the program is primarily a gynecologic oncology talk and program, and I spoke on sarcomas of the uterus. Uterine sarcomas are uncommon; they represent a collectively 3% or less of all uterine cancers, and uterine malignancies are challenging because it’s a group of diseases; leiomyosarcomas is one of the subtypes of uterine sarcomas.

For women who are diagnosed with these rare tumors, they can enter the health system in so many different ways—through gynecology, through gynecologic oncology, through medical oncology that’s part of gynecology, or through a soft tissue sarcoma medical oncologist that is not part of gynecology. We have this group of women who have rare diseases with care that can be fragmented because they can enter the system in so many different ways.

Could you expand on some of the available options?

As a field, there is a tremendous opportunity for collaboration between gynecologic oncology and sarcoma medical oncology to build bridges around what we understand—around what we need to learn, so that we can come together as a community, fundamentally, with patients at the center.Recent studies have suggested that gemcitabine-/docetaxel-based regimens, as well as anthracycline-based regimens, have activity in this disease. It is not about which one is better, per se, but women should know that there are multiple options available to them. [For example] olaratumab, a novel PDGFR-α antibody, was approved over the last couple of years in both the United States and in Europe. Again, it really highlights the importance of collaboration and communication in this field.

The diagnosis of a uterine leiomyosarcoma can be challenging. Are experts in the field working on new methods?

Olaratumab, when used with doxorubicin, demonstrated an overall survival (OS) advantage when compared with doxorubicin alone in patients with metastatic soft tissue sarcoma, including leiomyosarcoma. This improvement in OS led to the approval in the commercial availability of the drug, but it also comes with the requirement of a confirmatory phase III trial, which is currently underway. The study has completed its accrual and we are just waiting for the readout; it is something we will really be looking forward to. Olaratumab is also being studied in combination with other chemotherapies, just to see how we are going to exactly use this agent in soft tissue sarcoma, but also in the subset of women with uterine sarcomas.That is such a critically important question. There are many reasons that it is difficult to diagnose this tumor preoperatively. One, it is in contrast to endometrial carcinoma, which starts in the lining of the uterus; leiomyosarcoma starts in the wall of the uterus, so even though sometimes endometrial biopsies are performed [and] you can sometimes make the diagnosis, it’s just not a completely reliable strategy. This is because the tumors that are in the wall are not in the lining—it’s outside where the biopsy reaches.

Folks are looking at things such as novel diagnostic imaging and the optimization of MRI. For example, some people have looked at various blood tests to see if a combination of MRI with blood tests might help. To date, I would say that we still aren’t quite there yet.

Could you highlight other trials in this space?

Leiomyosarcomas are uncommon; based on what study you look at, it’s estimated that for women who undergo a hysterectomy for symptomatic fibroids, the risk of a leiomyosarcoma being identified is anywhere between 1 and 300 and 1 and 500. Some people might perceive that as sort of “a needle in a haystack,” but for the women who have leiomyosarcoma, that is a needle that we’re obligated to try and find, because it clearly impacts how they are treated, how we think about caring for them, and how we think about what their prognosis is.There is the phase III trial with olaratumab and doxorubicin; there are also studies in which olaratumab is being combined with other chemotherapies in soft tissue sarcoma. This is, again, to see if the benefit can be confirmed and [to see whether] it is unique to doxorubicin, or is it something that can be more broadly applied to cytotoxic chemotherapy in soft tissue sarcoma, including leiomyosarcoma.

There are some targeted therapies ongoing in leiomyosarcoma. One of the real challenges with that approach is that we don’t have a singular molecular driver of leiomyosarcoma for which to target. With that said, there are some biologic pathways that are thought to be potential vulnerabilities, including the PI3K pathway and potentially the mTOR pathway. Therefore, there are some ongoing studies looking in that arena. Certainly, immunotherapy is an area that is being explored to date. The majority of studies—of which there have been 4 that have included leiomyosarcoma with a checkpoint inhibitor—have not consistently shown dramatic results by any means. There is an opportunity for improvement that folks will start looking at: combination treatments.

Are researchers on the path to identifying any biomarkers?

There are also ongoing trials that I spoke about that build on other currently available cytotoxic chemotherapies. For example, trabectedin (Yondelis) has shown benefit and was approved for leiomyosarcomas, as well as liposarcomas. There are ongoing studies looking at doxorubicin plus trabectedin, particularly in leiomyosarcoma, based on some very interesting phase II data from the French Sarcoma Group that showed significant responses with that combination. That is something we will also be looking forward to.That is another really important question. Biomarkers can be a multitude of different things. Going back to diagnosis, is there something we can do to help identify the tumor preoperatively? That is something that is very intriguing; it’s something to evaluate. Pazopanib is a multikinase inhibitor, which clearly has activity in soft tissue sarcoma, as well as in leiomyosarcoma and in subsets of uterine leiomyosarcoma.

Could you expand on the need for more collaboration?

The challenge with pazopanib is it is a broad spectrum inhibitor and it hits lots of targets; we don’t know what the relevant target is in uterine leiomyosarcoma and because of that, it’s difficult to identify who the patients are that are likely to respond. Coming back to immunotherapy, that is another area in the oncology field, in general, where we need to do better. Who are those patients that will respond to immunotherapy with tumors that universally tend not to respond? [Meaning], in sarcomas in general, response rates are low but there clearly are reports of very dramatic responders here and there. We don’t yet know how to identify who those patients are; hopefully, we will get there.Again, I would emphasize collaboration. It is an uncommon tumor, patients can be treated by many different disciplines, and working together will help us all build on our strengths to bring the best to the patients. Leiomyosarcoma is not cured by chemotherapy, but there are certainly times when chemotherapy can play a significant role in controlling the disease and helping to improve quality of life. [We need to] help patients live with the disease in the best way possible for as long as possible, and that’s why we need to work together—collaboratively.

We also need to continue to work on fundamentals of biology and find areas of susceptibility and vulnerability of the tumor. That, to me, goes without saying that it is going to continue to happen for the science, but it’s up to us, as clinical teams, to work together to bring this to the patients.