A Phase I study of cinrebafusp alfa, a novel HER2/4-1BB bispecific antibody, has shown promising results in patients with HER2-expressing solid tumors. The first-in-human trial, published in Clinical Cancer Research, evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of cinrebafusp alfa in heavily pretreated patients. The study suggests that cinrebafusp alfa could offer a new therapeutic option for patients with HER2-positive cancers.
Study Design and Patient Population
The Phase I dose-escalation study enrolled patients with advanced HER2-expressing solid tumors who had progressed on prior therapies. Patients received cinrebafusp alfa intravenously every two weeks, with doses ranging from 0.3 to 15 mg/kg. The primary objectives were to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Secondary endpoints included assessment of pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity based on RECIST 1.1 criteria.
Safety and Tolerability
Cinrebafusp alfa demonstrated a manageable safety profile. The most common treatment-related adverse events (TRAEs) were cytokine release syndrome (CRS), fatigue, and rash. CRS was generally mild to moderate in severity and manageable with standard supportive care. The RP2D was established at 10 mg/kg every two weeks. "The safety profile observed in this study supports further clinical development of cinrebafusp alfa," noted Dr. [Fictional Name], lead investigator of the study.
Pharmacodynamic Effects
Pharmacodynamic analyses revealed dose-dependent increases in T-cell activation and proliferation in peripheral blood. Increased levels of cytokines, including IFN-γ and TNF-α, were also observed, indicating engagement of the 4-1BB co-stimulatory pathway. These findings suggest that cinrebafusp alfa effectively redirects T cells to HER2-expressing tumor cells, leading to immune-mediated tumor killing.
Clinical Activity
Encouraging anti-tumor activity was observed across various HER2-expressing cancers. Confirmed partial responses (PRs) were seen in patients with breast cancer and gastric cancer. Several patients experienced stable disease (SD) with tumor shrinkage. "We observed clinical benefit in heavily pretreated patients, which is encouraging," said Dr. [Fictional Name].
Implications for Future Research
This Phase I study provides a strong rationale for further investigation of cinrebafusp alfa in HER2-positive solid tumors. Ongoing clinical trials are evaluating its efficacy in specific cancer subtypes, including breast cancer and gastric cancer. The bispecific antibody represents a promising new approach to targeting HER2-expressing cancers and warrants further clinical development.
