More Effective Therapies Needed in Uterine Sarcomas

Richard Riedel, MD

There is a limited number of effective therapies for patients with uterine sarcomas, notably due to trouble accruing for clinical trials, disappointing data, and the rarity of the disease, explained Richard Riedel, MD.

For example, the phase III GOG-0277 trial was designed to evaluate adjuvant chemotherapy with gemcitabine and docetaxel (NCT01533207) followed by doxorubicin or observation in patients with high-risk uterine leiomyosarcoma previously removed by surgery. However, the trial was closed due to low enrollment.

Surgery remains the standard therapeutic option, said Riedel, an associate professor at Duke Cancer Institute; however, immunotherapy studies, while not promising thus far, are ongoing in an effort to have improved options.

In a phase II study, nivolumab (Opdivo) was evaluated in patients with advanced uterine leiomyosarcoma. Though designed to be a two-stage study, 0 of 12 patients enrolled in the first stage had a response, and the median progression-free survival (PFS) was 1.8 months.¹ Therefore, the second stage was closed.

However, findings from the phase II ALLIANCE A091401 trial demonstrated a benefit with the immunotherapy combination of nivolumab and ipilimumab (Yervoy) in patients with heavily pretreated, unselected, metastatic sarcoma. Data showed that there was an objective response rate of 16% (90% CI, 7-29), and responses were observed in uterine sarcoma.²

The FDA has approved a handful of targeted therapies for sarcomas, some of which include uterine sarcomas. For example, in October 2016, the FDA approved the PDGFRα antagonist olaratumab (Lartruvo) in combination with doxorubicin for the treatment of patients with advanced soft tissue sarcomas, including uterine leiomyosarcoma, for which a doxorubicin containing regimen would be appropriate.

In 2012, the FDA approved pazopanib (Votrient) for the treatment of patients with advanced soft tissue sarcoma who have previously received chemotherapy.

OncLive: What is the incidence of uterine sarcomas?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Reidel discussed the presentation and standard management of uterine sarcomas, the potential role of immunotherapy and targeted agents, and the challenges he hopes to overcome in the landscape in the near future.Reidel: Uterine sarcomas are extremely uncommon; they represent less than 5% of all uterine cancers. Even within that heading, there are a number of different subtypes, including adenosarcoma, endometrial stromal sarcomas of both low and high grade, perivascular epithelioid cell differentiation (PEC)omas, and undifferentiated uterine sarcomas and leiomyosarcomas. Despite the heading of uterine sarcomas, it really represents a number of different histologic subtypes with very clinical behaviors.

The treatment is evolving; surgery is still the mainstay for localized disease, radiation therapy will be used for local control. Chemotherapy can be considered, but in my opinion the data are not as robust as we would like. While there have been some encouraging data for using different regimens in different subtypes, such as gemcitabine and docetaxel for uterine leiomyosarcomas, a prospective study failed to accrue. As a result, it is not clear whether we will have a definitive answer as to whether adjuvant chemotherapy benefits that population.

How do uterine sarcomas typically present? Are there any challenges in diagnosing?

What is the emerging role of immunotherapy?

There is an emerging role of immunotherapy in sarcomas as a whole. What is clear is that, across a broad selection of patients, it may not be the “home run” that it is in more common cancers, such as melanoma and lung cancer. However, it is clear that there are certain subtypes that may benefit. It is not clear whether it will benefit patients with uterine sarcomas, but that still remains to be seen.The presentations can be varied. Many times, it can be abnormal uterine bleeding, which can result in an evaluation and identification of a mass. Oftentimes, unfortunately, uterine sarcomas are misdiagnosed as a uterine fibroid, which is actually a benign tumor. It’s not until it’s removed that the sarcoma is actually identified. The challenge is in the rarity of the disease; sarcomas, as a whole, represent about 1% of cancers in adults and uterine sarcomas are less than 5% of all cancers in general. Therefore, 99% of the time, a uterine mass is going to be a uterine fibroid as opposed to a uterine sarcoma. Those are some of the challenges—the rarity and there can be some nonspecific symptoms.I’m not aware of a trial specifically in uterine sarcoma. There was a phase II study that was published recently from our colleagues at Dana-Farber Cancer Institute looking at the role of nivolumab in uterine leiomyosarcoma. It was designed to be a two-stage study, but in the first stage only 12 patients were enrolled and the median PFS was less than 2 months. It was certainly disappointing, and as a result the second stage never enrolled.

Immunotherapy in sarcoma is currently being looked at in a number of different histologies, including leiomyosarcomas that are not uterine specific and soft tissue sarcomas; again, the results have been fairly disappointing. In a study called SARC028, which looked at pembrolizumab (Keytruda), the response rates for leiomyosarcomas were essentially 0%. However, it was a small cohort of patients; only 9 or 10 patients were enrolled on that cohort.

Are there any targeted agents or even molecular targets in development?

In a recently published study, which looked at nivolumab with or without ipilimumab there were responses in both uterine and nonuterine leiomyosarcomas. There are ongoing expansion cohorts trying to further identify whether there is actually a signal there or not.Pazopanib is FDA approved for the treatment of sarcomas; it was approved in 2012 for a broad range of soft tissue sarcomas, uterine sarcomas included. That was based on the phase III PALETTE study. The response rates for pazopanib are low, but the benefit is really in disease control. More recently, trabectedin (Yondelis) was approved in late 2015 for leiomyosarcoma and liposarcoma. We don’t often see liposarcomas being in the uterus, but we certainly see leiomyosarcomas. That phase III study was based on an improvement in PFS compared with dacarbazine, an active comparator.

What are the differences between leiomyosarcomas and liposarcomas?

In the next 5 years, what would you like to see accomplished for uterine sarcomas?

We have made some advances with those agents; most recently olaratumab was approved in 2016 to be used in combination with doxorubicin. That was based on a phase II study in which the combination showed an improvement in overall survival compared with doxorubicin alone. The magnitude of improvement was 11.8 months, which was an impressive survival benefit. Based on that study, the FDA approved olaratumab to be used in combination with doxorubicin but required a phase III study, which has been performed. It’s called the ANNOUNCE study and results are still pending. With respect to approved agents, we had pazopanib in 2012, trabectedin in 2015, and olaratumab in 2016. Another medicine called eribulin (Halaven) was approved and that was for liposarcomas only, so it may not be relevant for the uterine sarcoma population.Most cancers, in general, are named for organs that they start in. Sarcomas arise from the connective tissue—things like muscle, bone, fat cartilage, nerves, and blood vessels—and as a result they can occur anywhere in the body. Lipo means fat, so a liposarcoma is a cancer that has features of fat. Leio means smooth and myo means muscle; a leiomyosarcoma is one that has features of smooth muscle. That is how we name the sarcomas—based on the normal tissue counterparts they resemble.What I would like for uterine sarcomas mirrors what I want for sarcomas in general, which is more effective therapies. The number of therapies we have is limited; the effectiveness of those therapies is limited, as well. I would have loved to have seen a study fully accrue and show a benefit for adjuvant chemotherapy in uterine leiomyosarcomas. However, as I mentioned, it is unlikely to happen based on the results of the GOG-0277 study.

Is there anything else you would like to emphasize?

[Moreover, we need to understand] the underlying pathology of the individual subtypes; for example, PEComa is a subtype that is seen in the uterus and is an entity that doesn’t respond to conventional cytotoxic chemotherapy. It does, however, respond to mTOR inhibition and there is an ongoing multicenter phase II study looking at a second-generation mTOR inhibitor intravenously as part of a registrational study. If successful, we may have a therapy specifically for PEComas, which would then be relevant for PEComas that start in the uterus.The only thing I would recommend is that if there is a suspicion for a sarcoma, patients should be seen and managed in centers with expertise. We know that patients who are seen in academic centers have better outcomes and have access to multidisciplinary approaches, which can result in better outcomes for our patients.

References

1. Ben-Ami E, Barysauskas CM, Soloman S, et al. Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: results of a phase 2 study. Cancer. 2017;123(17):3285-3290. doi: 10.1002/cncr.30738.
2. D’Angelo SP, Mahoney MR, Van Tine BA, et al. A multi-center phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401). J Clin Oncol. 2017;35(suppl; abstr 11007).