HER2-targeted radioimmunotherapy regimen achieves complete and durable response in breast cancer model

A new radioimmunotherapy approach has the potential to cure human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to new research published in the November issue of The Journal of Nuclear Medicine. The regimen, which pre-treats the tumor before delivering targeted alpha-radioimmunotherapy, resulted in durable major responses—including histologic cures—with minimal toxicities, paving the way for a safer and more effective treatment option for breast cancer patients.

Advanced metastatic breast cancer has a poor prognosis, especially for highly aggressive HER2-positive subtypes. HER2 is an oncogene that is overexpressed in 15–20% of breast cancers and is a clinically established therapeutic target. Although current HER2-targeted therapies offer improved outcomes, challenges remain because of treatment-related adverse events and tumor resistance to treatment.

“Previous studies have shown that HER2-targeted radioimmunotherapy with the α-particle-emitting radionuclide ²²⁵Ac has been effective, but not safe, as alpha-particles were retained in the body, resulting in high toxicities,” noted Sarah Cheal, Ph.D., assistant professor at Weill Cornell Medicine in New York. “In our study, we used a pretargeted radioimmunotherapy (PRIT) approach to directly treat the tumor and prevent potent alpha-particles from being absorbed in healthy tissues.”

The radioimmunotherapy treatment approach consisted of a three-step intravenous regimen: first a bispecific anti-HER2/anti-DOTA antibody, next a clearing agent, and finally ²²⁵Ac-Pr radioimmunotherapy. Researchers began by testing the effects of ²²⁵Ac-Pr dosing during PRIT on tumor-targeting efficiency and tissue biodistribution in a BT-474 breast cancer xenograft model.

The regimen was then evaluated in mice bearing the BT-474 xenograft or a patient-derived xenograft. The mice were treated with either one or two cycles of ²²⁵Ac-PRIT separated by one week. A dose escalation study was also performed on the BT-474 model to establish the nephrotoxic absorbed radiation dose.

In the BT-474 model, 100% of mice achieved complete responses and 85% achieved histologic cure. One-cycle and two-cycle treatments were equally effective. Treatments were well tolerated, with no chronic radiation toxicity documented. In the patient-derived xenograft model, a single ²²⁵Ac-PRIT treatment led to 60% complete response and prolonged survival versus no treatment. Lastly, researchers identified the dose in the ²²⁵Ac-PRIT regimen at which severe chronic nephrotoxicity was induced.

“This study illustrates the curative potential of ²²⁵Ac-PRIT as a treatment for highly aggressive subtypes of HER2-positive breast cancer,” said Nai Kong Cheung, MD, Ph.D., member and attending physician in Pediatric Oncology at Memorial Sloan Kettering Cancer Center in New York. “If successfully translated to the clinic, HER2-directed ²²⁵Ac therapy could offer new treatment options in breast cancer and other HER2-expressing solid tumors.”

Provided by
Society of Nuclear Medicine and Molecular Imaging