Dr Secord on Combining Mocertatug Rezetecan With Dostarlimab in Endometrial Cancer

“The antibody-drug conjugates that target FRα or HER2, for example, are targeting proteins that are involved in growth regulation signals, whereas B7-H4 is a bit different because it’s more involved in the immune system.”

Angeles Alvarez Secord, MD, MHSc, professor of obstetrics and gynecology, Obstetrics and Gynecology, and member of Duke Cancer Center at Duke Cancer Institute, discussed the rationale behind the phase 1/2 BEHOLD-2 trial (NCT06796907) evaluating mocertatug rezetecan (Mo-Rez) in combination with dostarlimab-gxly (Jemperli) in patients with endometrial cancer.

Secord expressed enthusiasm for antibody-drug conjugates (ADCs) broadly, noting that the B7-H4–targeted ADC class stands apart mechanistically from agents targeting FRα or HER2, which act on growth-regulation signaling. B7-H4, by contrast, plays a role in immune regulation, she explained, and mocertatug rezetecan is also being evaluated in ovarian cancer alongside its investigation in endometrial cancer. In module 1, the focus will be on patients who have received a diagnosis of endometrial cancer with confirmed mismatch repair–proficient or microsatellite stable tumor status by local test. These patients must have experienced disease progression or intolerance to at least 1 line of standard prior systemic therapy and be ineligible for curative external radiotherapy or brachytherapy.

Secord highlighted the potential to upregulate immune activity in traditionally “cold” tumors that don’t typically respond to immunotherapy, as well as in patients previously exposed to immunotherapy. She described the mechanism as counterintuitive at first glance: by suppressing the immune-suppressive effects within the tumor microenvironment, the ADC ultimately drives increased immune stimulation.

Secord explained that combining mocertatug rezetecan with dostarlimab creates a synergistic effect. The B7-H4–directed ADC generates immune stimulation and potential cell kill, which in turn increases neoantigen release, she said, creating conditions where dostarlimab can then amplify the immune response even further. This combined mechanism, Secord noted, is what distinguishes this approach from other ADC and immunotherapy combinations currently under investigation.