Singh Discusses Developments in Uterine Sarcoma

Arun S. Singh, MD

There are approximately 60 types of soft tissue sarcoma, with about 10,000 cases diagnosed yearly in the United States. The rarity of most subtypes has been an impediment to basic and clinical research and development in the field, said Arun S. Singh, MD. However, recent developments are starting to provide hope for patients with these rare diseases.

“In the last few years, pharmaceutical companies have become involved in doing trials in these rare malignancies,” Singh explained. “That has the allowed the development of several new drugs for soft tissue sarcomas, including uterine leiomyosarcoma.”

In October 2016, the FDA granted an accelerated approval to 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 the phase II JGDG study, the combination decreased the risk of death by 48% versus doxorubicin monotherapy (HR, 0.52; 95% CI, 0.34-0.79, P <.05). Olaratumab is now being tested in an ongoing trial in combination with gemcitabine and docetaxel in patients with advanced soft tissue sarcomas including leiomyosarcoma (NCT02659020).

OncLive: What therapies are available to treat patients with uterine sarcomas?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Singh, an associate professor in the Department of Medicine, Division of Hematology/Oncology, at the University of California, Los Angeles, discussed current and emerging treatment strategies for patients with uterine leiomyosarcoma and other sarcomas.Singh: Sarcomas are a very rare group of malignancies. They are connective tissue cancers that can occur anywhere in the body. They occur in the uterus, as well.

What is the prevalence of these cancers?

Can you elaborate on the available treatments for patients who have these cancers?

What are some combinations are being explored?

What are some of the issues with how leiomyosarcomas are diagnosed?

Traditionally, these diseases are treated with surgery and sometimes radiation therapy. There is definitely a role for systemic treatment, particularly in people who have advanced-stage disease. My presentation focused on new chemotherapies and some targeted therapies for uterine leiomyosarcoma and I also touched on the early data of immunotherapeutic approaches for this disease. All in all, there are about 60 different types of soft tissue sarcomas. If you add them all up, there's only 10,000 cases a year in the United States. There are just a few hundred cases of each type of sarcoma. Leiomyosarcoma is one of the more common sarcoma subtypes and accounts for about 20% of all sarcomas; these smooth muscle tumors most commonly originate in the extremities, the uterus and from large blood vessels.Systemic agents for sarcomas involve chemotherapies, targeted therapies and experimental immunotherapeutic approaches. Several chemotherapies can be used to treat leiomyosarcoma including doxorubicin (alone or in combination with olaratumab), gemcitabine and docetaxel, ifosfamide, trabectedin, and dacarbazine. The targeted therapy pazopanib (Votrient) has been used for soft tissue sarcomas and is effective in leiomyosarcoma. Currently, the development of immunotherapy is in its infancy. There have been only small clinical trials that have been done of checkpoint blockade for leiomyosarcoma with marginal results. At this time, we are still learning how to pick the right patients for these trials. Currently, the most exciting combination is the addition of olaratumab, which is a PDGFRα antibody, to gemcitabine and docetaxel. That is in an ongoing trial. The FDA approved olaratumab based on a phase II trial for soft tissue sarcoma, including uterine leiomyosarcoma.A lot of leiomyosarcomas are presented at later-stage disease. Moreover, the grading is not always predictive of the clinical behavior of this disease. Those are some of the issues. The other issue with uterine leiomyosarcoma is its overlap with fibroids. Fibroids are a very prevalent problem everywhere. Millions of women have fibroids. Fibroids are smooth muscle growths, and leiomyosarcoma means smooth muscle cancer.

What research needs to be done in the field?

There are several cases of patients having surgeries thinking they have a fibroid only to come out after surgery to find that they have a leiomyosarcoma. That is probably the biggest problem in deciding how to treat the disease because the surgery for a fibroid removal is considerably different than the surgery for a leiomyosarcoma removal. One area that needs more high quality studies is of the use of chemotherapy in the adjuvant setting for patients who have had surgery for uterine leiomyosarcoma. We know that most patients who have a uterine leiomyosarcoma have about a 50% to 70% chance of recurrence, even if the best surgery is done.

You would imagine that this is an easy area to do a clinical trial in. However, only 2 good clinical trials have been done, and they only enrolled a small number of patients.

In what other area would you like to see further development?

There was a trial by the Gynecologic Oncology Group that sought to address this question. However, they had such poor accrual that the trial was closed. We don't fully know the answer because we don't have what is called Level I evidence or high quality evidence of the efficacy of chemotherapy in this setting. As such, we can’t tell patients that chemotherapy is clearly indicated after surgery for uterine leiomyosarcoma. Some of it is left to expert opinion at this point and having a balanced discussion about the risks and benefits of adjuvant chemotherapy after resection for uterine leiomyosarcoma. Certainly, identifying the immune factors in the leiomyosarcoma tumor microenvironment. There are ongoing studies showing that there are a lot of tumor-associated macrophages that infiltrate leiomyosarcomas. The real question is, “What are they doing there? Are they truly immunosuppressive or are they doing something good?” We don't know the answer to that as of yet. If we find that they are immunosuppressive, that might be an avenue for figuring out how to attack leiomyosarcomas from an immunologic standpoint.

Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-497. doi: 10.1016/S0140-6736(16)30587-6.