A Phase II clinical study in women with advanced cervical cancer found that 22% of the patients treated with the bispecific antibody, bintrafusp alpha, experienced a tumor response, with 56% of these patients responding consistently for six months or more. The trial, published in JAMA Oncology, included 146 women in the U.S., China, France, Germany, Japan, and Korea, whose cancer had progressed during or after platinum-based chemotherapy.
Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor (TGB β) fused to immunoglobulin G1 antibody blocking programmed cell death 1 ligand 1 (PD-L1).
“There’s good news and bad news in cervical cancer from a therapeutic standpoint,” according to Michael Birrer, MD, PhD, senior author of the study. The good news is that we know that anti-PD-L1 therapy works. The bad news—if look at Keynote 158 which was the first study that showed it—is that the response rate was about 12%.” Looking closely, the PD-L1-positive subset, one of the targets for anti-PD1 therapy went up only to 14%. “It was a mystery to us why the response rate was so low.”
Realizing that some people do response to immunotherapy, Birrer’s team sought to evaluate other immunotherapy targets. “That is how we became interested in the bispecific antibody that included targeting the TGB β receptor,” he explains. “It was originally thought to be a tumor suppressor gene. We now know that many cancers switch from using TGB β to control growth to where it stimulates growth.” Because of this switch, Birrer says that TGB β has gone through a long, torturous biologic story, and now agents are being developed to target it.
Targeting TGF β also made sense in this study since most cervical cancers are driven by the human papillomavirus (HPV), which has been linked to the upregulation TGF-β signaling.
The team did see a better overall response than just 14–15% with anti-PD-L1 observed in the Keynote study. The confirmed objective response rate was 21.9%. More significantly, 59.4% of these responses were durable, lasting six months or more. At the time of data cutoff, responses were still ongoing in 40.6% of the responders.
“Perhaps most importantly, the median duration of response has not even been reached, so those patients who respond actually do exceedingly well,” Birrer says.
Cervical cancer remains a significant health challenge, especially for women worldwide, with approximately 660,000 new cases and 350,000 deaths annually. Despite advancements in medical research, the disease continues to claim thousands of lives each year. In the United States alone, an estimated 13,820 women will be diagnosed with cervical cancer this year, and 4,360 will succumb to it.
This study is particularly relevant given the demographic disparities in cervical cancer incidence and outcomes. The disease disproportionately affects underserved minorities, including Hispanic and African American populations, who often lack access to routine gynecological care.
The significance of these findings is underscored by the limited treatment options available for recurrent or metastatic cervical cancer. Current treatments often involve chemotherapy, which typically yields poor response rates and a grim overall survival rate of about 10 months. Only two FDA-approved treatments exist, neither of which are curative.
“This is a very positive trial, but I think the more important issue is the fact that the bispecific antibody targets TGB β, and that’s a home run,” says Birrer. “It had fallen out of favor as a therapeutic target, and this study provides a very strong argument that in selected tumors, TGB β is an important player, and you can get reasonable response rates and durations if you target it.”
The study did reveal that the overall survival rates were considerably higher in squamous cervical cancer (16.8 months), as opposed to adenocarcinoma (9.1 months). “We weren’t surprised by that, but it’s important to know,” Birrer adds. If we went back and did a squamous-only study, my guess is the response rate would be 30 to 40%, so there may be meaningful subsets of patients clinically and pathologically determined who would benefit the most from this kind of approach.
Given these results Birrer cites that the most logical step forward would be to combine inhibition of TGB β—perhaps with this bispecific antibody or other methods—with chemotherapy. “Chemotherapy is still used for recurrent cervical cancer, and my guess, assuming the toxicities don’t overlap—which they really don’t—is that the response rate will be considerably higher, probably 30 to 40% and the duration of response may even be longer.”
