Regorafenib as maintenance therapy showed significant delayed progression of non-adipocytic soft tissue sarcomas

Because advanced non-adipocytic soft tissue sarcomas (STSs) are aggressive with poor outcomes, the goal of treatment is to delay progression and ensure quality of life. Doxorubicin (an anthracycline chemotherapy) is first-line standard of care for these patients. Researchers have discussed whether adding maintenance therapy might improve progression-free survival (PFS), but few studies have examined the option.

Non-adipocytic STSs are cancers that start in the body’s connective tissues but not in fat cells (which are called adipocytes).

EREMISS, a double-blind, randomized, controlled, phase 2 trial, evaluated the safety and PFS of maintenance therapy with regorafenib in patients with non-adipocytic STSs. Findings showed that regorafenib significantly increased PFS after first-line treatment by a median difference of 2.1 months. Results were published in the Annals of Oncology (doi:10.1016/j.annonc.2025.03.024).

“The sarcoma community has had a lot of conversation around the role of maintenance, and I was really pleased to see this well-designed study,” says Lara Davis, MD, an associate professor of medicine in the Division of Hematology/Medical Oncology and the director of the Sarcoma Program at Oregon Health & Science University in Portland. “The findings are clearly significant and look very promising. While the role of maintenance therapy in general is not fully established, it’s absolutely worth additional investigation.”

The EREMISS trial assessed the activity and safety of regorafenib in 126 patients with advanced non-adipocytic STSs who were enrolled in 17 centers in France from May 2019 to November 2022.

Regorafenib is an oral multikinase inhibitor that can target oncogenic pathways. Studies have shown its effectiveness in treating some sarcoma subtypes, aside from liposarcomas.

Female patients represented 55% of the total enrollment, and the median age was 58 years. The most common subtype was leiomyosarcoma (59%).

Participants who had stable disease or a partial response after six cycles of doxorubicin as a first-line treatment received 120 mg of regorafenib per day for 3 weeks on and 1 week off. The primary end point was PFS. It was accessible in 122 patients.

The median PFS by blinded central review was 3.5 months in the placebo arm and 5.6 months in the regorafenib arm. Although overall survival was not the primary end point, it was 20.5 months for the placebo group and 27.6 months for the regorafenib group.

In the placebo arm, 4.8% of the patients experienced grade 3 or higher adverse events, whereas 56.3% of the patients receiving regorafenib did. The most common adverse events were asthenia (9%), atrial hypertension (8%), and rash (8%).

Robin Jones, MD, a medical oncologist and sarcoma specialist at the Royal Marsden Cancer Center in London, praises the study’s design.

“The authors should be congratulated for actually completing and publishing the trial given the challenges posed by the Covid-19 pandemic,” he says. “My view is that this therapy probably does help a subgroup of patients, but we currently don’t have a good way of identifying those patients—it’s a very personal discussion between the treating oncologist and the patient in terms of the pros and cons of treatment.”

Dr Davis notes that although the study findings are encouraging, applying the results to clinical practice is challenging.

“The majority of our data in the sarcoma field is based on phase 2 trials,” she says, noting the difficulty of finding large groups of patients to conduct phase 3 trials in these relatively rare cancers.

As a result, US sarcoma clinicians often rely on phase 2 trial results for treatment guidance, but a lack of phase 3 data on regorafenib could limit insurance coverage as well as its incorporation into National Comprehensive Cancer Network (NCCN) guidelines, Dr Davis adds.

“I would hope that the NCCN guidelines panel would take into consideration the results of this study and consider adding regorafenib maintenance therapy as an option,” she says. “I think this study has more evidence behind it than some of the therapies that are listed, but I don’t think it’s a shoe-in.”

In many European countries, it is unlikely that clinicians will be able to prescribe off-label regorafenib for maintenance therapy without a phase 3 trial demonstrating its efficacy, Dr Jones says.

“It’s impossible to perform a large, randomized phase 3 trial for every rare sarcoma. For example, only about 10 people are diagnosed with some rare sarcoma subtypes in the UK each year,” he adds.

Although some patients live many years with the disease, the wide variations in survival rates and aggressiveness for different sarcomas make it all the more difficult to conduct clinical trials, Dr Jones notes.

In the United States, however, regorafenib could potentially be prescribed off-label, according to Dr Davis.

“We’re very lucky here in that we have the ability to make some personalized recommendations for our patients,” she says.

Some patients who have stable disease after six cycles of doxorubicin, and who are mentally and physically ready for a treatment break, may want to try maintenance therapy. Others who are feeling okay may want to continue being as aggressive as possible with chemotherapy, she notes.

Another caveat for regorafenib is its well-known toxicity profile, as evidenced by the more than 56% of patients experiencing grade 3 or higher adverse events in the study. Many patients simply will not tolerate it even at a reduced dose, Dr Davis says.

Sarcoma specialists also have discussed launching new clinical trials to assess whether switching maintenance therapies during treatment may reduce toxicity while achieving similar or better outcomes.

One approach might be following doxorubicin as a first-line therapy with the chemotherapy drug trabectedin for maintenance.

“Trabectedin doesn’t have the cumulative toxicity profile as other drugs and can be continued sometimes even for years,” Dr Jones says.

He emphasizes the importance of more clinical trials like EREMISS to ensure better treatment options for rare cancers and to identify subgroups of patients who could benefit from specific therapies.

Sharon Eppley, who developed radiation-induced angiosarcoma after radiation for her breast cancer, is one patient who could potentially benefit from such new studies. After her complex treatment for the disease, she had hoped there might be a maintenance therapy available, but physicians told her there were no current options. Nor is she sure she would elect to go for one if there were.

“It would certainly have to be a studied answer,” she says. “Now that I’ve actually had metastatic sarcoma friends who’ve died from the chemotherapy or the treatment related to it, I think I’m more prudent in my judgment. I would ask what the odds are for how many more years I could live.”