A potent combination of two immunotherapy drugs is providing new hope for people with sarcomas — a rare cancer that develops in the bones, muscles, blood vessels, and other connective tissue — that don’t respond well to other types of immunotherapy.
“We've been running a phase one, multi-site trial that has had a tremendous amount of enrollment, and the take-home message is that these drugs tend to work better for cancers where traditional immunotherapy doesn't work,” says University of Colorado Cancer Center member Breelyn Wilky, MD, principal investigator for the phase one study. “We are extending the reach of the immunotherapy to ‘cold tumors,’ or tumors that are not particularly well recognized by the immune system.”
One of the drugs in the experimental combination is botensilimab, an investigational antibody that blocks a molecule called cytotoxic T-lymphocyte antigen 4 (CTLA4).
“I describe CTLA4 as the molecule that helps T cells learn from our macrophages and dendritic cells about what they should be killing,” Wilky says. “It’s an early education checkpoint.”
The second drug, balstilimab, is a monoclonal antibody that binds to the programmed cell death 1 (PD-1) receptor on T-cells, preventing a tumor from sending signals that prevents a T cell from attacking it.
“When you already have T cells that know what they're supposed to be killing, and they're face to face with the tumor cell, blocking PD 1 gets rid of that checkpoint where the tumor says, ‘Don't eat me,’” Wilky says. “When you get rid of that, the immune cells that are already educated can then kill the tumor cell.”
Patients in the clinical trial take both drugs together in sequence — balstilimab every two weeks and botensilimab every six. So far, the treatment is working reasonably well for all sarcoma patients, but it is working especially well for patients with the blood vessel sarcoma known as angiosarcoma.
“The response rate was 23% for all of the sarcoma patients, but we are really excited about the results in the angiosarcoma subtype, which is very hard to treat,” says Wilky, who recently presented data from the study at the European Society for Medical Oncology Congress in Barcelona. “We got a 44% response rate in that group in particular, which is promising, because that's generally a super-immune cold tumor where we wouldn't have expected immunotherapy to work.”
A specific trial for patients with angiosarcoma could happen down the road, Wilky says; more immediately, she also is overseeing a separate trial to see if the balstilimab-botensilimab combination, along with chemotherapy, shows promise in patients newly diagnosed with sarcomas.
“There's no approved checkpoint inhibitor for sarcomas, so there is a huge unmet need,” she says. “We've had patients in both trials with metastatic sarcoma who historically would never have been cured. Chemo could slow it down, but they wouldn't be cured.”
If the drug combination is approved in either scenario, Wilky says, it would open the door to further testing on other sarcomas.
“Once we have an approval, it would be wonderful to be able to explore this more in other types of sarcomas,” she says. “We saw patients with leiomyosarcoma, a rare cancer that grows in smooth muscles, get benefit in the study where normally we would not expect responses to immunotherapy. We're going for the populations where we can really home in on the signal and get it moving forward as best we can.”